RARE DISEASE
Middle East respiratory syndrome
Middle East respiratory syndrome
Middle East respiratory syndrome
Synonyms: MERS
Synonyms: MERS
Synonyms: MERS
Drug discovery
2
drugs
With orphan designations
Overview
Middle East respiratory syndrome (MERS) is a severe viral illness caused by MERS-coronavirus, first identified in 2012. It presents with fever, cough, dyspnea, and pneumonia, progressing to acute respiratory distress syndrome (ARDS) in 35% of cases [1][6][17]. Transmission occurs via camel exposure or healthcare-associated human-to-human spread, with a case fatality rate of 35-39% [2][6][16].
Population
84% of cases occur in Saudi Arabia; others linked to travel/residence in Bahrain, Jordan, UAE, or Yemen [6][9][12].
High-risk groups: Older adults (≥65 years), immunocompromised individuals, and those with diabetes, renal disease, or cardiopulmonary conditions [4][12][17].
25% of cases involve healthcare workers during outbreaks [1][7][11].
Burden
Mortality: 35-39% among lab-confirmed cases, rising to 45% in patients ≥65 years [2][4][12].
Healthcare impact: 50% of secondary cases linked to hospital outbreaks, straining ICU capacity [6][7][9].
Economic: Outbreaks disrupt healthcare systems; 2015 South Korea outbreak cost $8.5 billion [5][9][17].
Therapies
Supportive care: Oxygen therapy, mechanical ventilation, and ECMO for severe ARDS [1][8][13].
Antivirals: Limited efficacy data for ribavirin/interferon combinations; no approved targeted therapy [3][14][18].
Infection control: Strict PPE and isolation protocols to curb nosocomial transmission [1][9][12].
Categories: rare infectious diseases, rare respiratory diseases
Research Papers
1,419 drug discovery papers about Middle East respiratory syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,419 drug discovery papers about Middle East respiratory syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-20 | Reduced DPP4 Binding Confers Resistance to Soluble DPP4 While Preserving MERS-CoV Entry into Cells Expressing High Levels of DPP4
ABSTRACT The Middle East respiratory syndrome coronavirus uses DPP4/CD26 as receptor for cell entry. Soluble recombinant DPP4 can block MERS-CoV infection in cell culture and in animal models and might hold promise as antiviral. Furthermore, endogenous soluble DPP4 in plasma might reduce MERS-CoV dissemination in infected individuals. Therefore, we addressed whether and how MERS-CoV can acquire resistance against soluble DPP4 (sDPP4), employing a vesicular stomatitis virus (VSV) encoding the MERS-CoV spike (S) protein (VSV-MERS-S). Passaging of VSV-MERS-S in the presence of sDPP4 selected for viral variants with mutations L507I and L507H in the receptor binding domain (RBD) of the S protein. These mutations reduced sDPP4 binding, were compatible with robust entry into cell lines expressing high levels of DPP4 and conferred sDPP4 resistance. In contrast, entry into cell lines expressing low levels of DPP4 was reduced. Furthermore, polymorphisms L507F/R/P, which were detected in MERS-CoV sequences from patients, exhibited an even more pronounced phenotype, with L507R and L507P conferring complete sDPP4 resistance. Collectively, our results show that naturally occurring polymorphisms in the MERS-CoV S protein can confer sDPP4 resistance by reducing sDPP4 binding but might still be compatible with robust viral spread in cells and tissues expressing high levels of DPP4. IMPORTANCE DPP4 is the cellular receptor used by MERS-CoV for entry into target cells. A soluble form of DPP4 (sDPP4) blocks MERS-CoV infection and has been proposed as a potential antiviral. Here, using surrogate systems, we show that MERS-CoV can acquire resistance to sDPP4 through spike protein mutations that reduce DPP4 binding. These mutations remain compatible with efficient entry into cells expressing high levels of DPP4 and were also identified in patient-derived MERS-CoV. Our findings suggest that MERS-CoV can balance receptor engagement with resistance to a soluble receptor decoy, with implications for antiviral strategies targeting virus-receptor interactions.
2026-06-23 | Broadly Protective Antibody-Like Vaccines Against Highly Pathogenic Coronaviruses.
SARS-CoV-2 and MERS-CoV are highly pathogenic and contagious coronaviruses. Despite intensive vaccination, SARS-CoV-2 continues to spread, and no FDA-approved vaccines exist for MERS-CoV; thus, more effective and safer vaccine options are needed. The receptor-binding domain (RBD) of coronaviruses is a primary target of neutralizing antibodies (nAbs); therefore, we generated three bivalent IgG1 Fc-fusion vaccines (BiVaxs) combining SARS-CoV-2 and MERS-CoV RBDs. The BiVaxFc-Native vaccine comprises omicron's-RBDSARS-CoV-2 fused to the native Fc C-terminus and RBDMERS-CoV to the N-terminus. The BiVaxFc-Reverse vaccine has a native Fc, yet RBDMERS-CoV was fused to the C-terminus, and the omicron's-RBDSARS-CoV-2 to the N-terminus. The third was BiVaxFc-FcRn, which is similar to BiVaxFc-Native, although it contains MST-HN Fc mutations (M252Y/S254T/T256E-H433K/N434F) to enhance neonatal Fc receptor (FcRn) binding on antigen-presenting cells (APCs). In mice, BiVaxFc-FcRn showed significantly higher immunogenicity than the other two forms. It induced robust IgG and nAb responses against RBDMERS-CoV after two doses and moderate responses omicron's-RBDSARS-CoV-2 after the third dose. Remarkably, it also generated strong cross-reactive antibodies against SARS-CoV-1. These findings suggest that RBDMERS-CoV is more immunogenic than omicron's-RBDSARS-CoV-2, and that BiVaxFc-FcRn has a high potential for further development as a broad-spectrum vaccine platform to prevent infection with the targeted coronaviruses as well as future emerging viruses.
2026-06-12 | Cleavage of TOM1 by the SARS-CoV-2 main protease NSP5 prevents autophagic degradation of viral envelope.
Autophagy plays a critical role in viral replication and the regulation of host immune responses. Although the TOM1-TOLLIP complex has been implicated in immune signaling, cargo trafficking, and endocytosis, its role in viral replication has not been defined. Here, we demonstrate that the SARS-CoV-2 main protease (NSP5) cleaves TOM1 at residue Q354 through its protease activity. This cleavage is also observed with the main proteases of SARS-CoV and MERS-CoV. Importantly, TOM1 overexpression suppresses SARS-CoV-2 replication in HEK293T-hACE2 and Vero cells, while TOM1 knockout via CRISPR-Cas9 significantly enhances viral propagation, indicating that TOM1 functions as a novel restriction factor against SARS-CoV-2 infection. Moreover, various TOM1 orthologs from diverse species, including cattle, bats, monkeys, mice, and ducks, show similar restriction to SARS-CoV-2, but they all are antagonized by NSP5 cleavage. Mechanistically, we found that TOM1 recruits the autophagy receptor TOLLIP to target SARS-CoV-2 envelope (E) protein for autophagic degradation, thereby limiting viral replication. These findings highlight the importance of the TOM1-TOLLIP complex in host defense and discover that SARS-CoV-2 exploits a conserved NSP5-mediated TOM1 cleavage mechanism to evade host antiviral defenses.IMPORTANCEViruses must overcome the body's natural defenses in order to replicate and spread. One important cellular defense mechanism is autophagy, a process that helps cells remove harmful proteins and pathogens. In this study, we discovered that a host protein called TOM1 acts as a restriction factor that helps limit the replication of SARS-CoV-2, the virus responsible for COVID-19. TOM1 works together with another protein, TOLLIP, to direct envelope proteins to the cell's degradation system, thereby reducing viral replication. However, SARS-CoV-2 has evolved a strategy to counter this defense. The viral main protease (NSP5) cleaves TOM1, disabling its antiviral activity. This mechanism is conserved among several coronaviruses, including SARS-CoV and MERS-CoV. Our findings reveal a previously unrecognized antiviral role of the TOM1-TOLLIP complex and demonstrate how coronaviruses evade this host defense, providing new insight into virus-host interactions and potential targets for antiviral therapies.
2026-05-27 | Modulation of Host Innate Immune Response by Highly Pathogenic Human Coronaviruses during Viral Infection.
Highly pathogenic human coronaviruses, including SARS-CoV, SARS-CoV-2, and MERS-CoV have emerged as significant public health threats due to their ability to cause widespread outbreaks and pandemics. These viruses induce dysregulated inflammatory responses, typified by cytokine storms that drive extensive tissue damage in pulmonary and extrapulmonary systems, leading to acute respiratory distress syndrome (ARDS) and multi-organ failure. These pathological outcomes are driven by sophisticated mechanisms that manipulate host immune pathways and evade innate and adaptive immune surveillance. The innate immune system plays a pivotal role in the early detection and control of viral infections through mechanisms such as cytoplasmic RNA sensors, Toll-like receptors, interferon signaling, and inflammasome activation. However, these coronaviruses effectively exploit and subvert these processes, suppressing antiviral defenses while amplifying inflammatory cascades. This review delineates the molecular and cellular strategies employed by these pathogens to evade immune recognition and exacerbate immune-mediated tissue injury. Understanding these processes is fundamental for guiding the development of targeted antiviral interventions, immunomodulatory therapeutics, and robust strategies to mitigate the impact of future coronavirus pandemics.
2026-05-05 | Targeting Middle East Respiratory Syndrome Coronavirus Spike Fusion Machinery With Antiviral Peptides: In Silico Exploration of the Heptad Repeat 2 Domain.
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) remains a significant global health threat, necessitating the development of effective antiviral therapeutics. Targeting the heptad repeat 2 (HR2) domain of the MERS-CoV spike protein offers a promising strategy to inhibit viral fusion and entry into host cells. This study investigates a panel of antiviral peptides (AVPs), focusing on Griffithsin, Brevinin-2, and CCL20, to evaluate their potential as fusion inhibitors against the HR2 domain. Employing comprehensive computational approaches, including molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy calculations, we characterized the peptide-protein interactions and stability of these AVPs in complex with HR2. Our results demonstrate that Griffithsin, Brevinin-2, and CCL20 exhibit stronger binding affinities (- 213.69, -168.83, and -165.17 kcal/mol, respectively) compared to the standard inhibitor Peptide-6 (- 49.73 kcal/mol). MD simulations reveal stable complexes and indicate disruption of critical hydrogen bonds in the Ile1255-Gln1271 region of HR2, essential for six-helix bundle formation and viral fusion. Physicochemical analyses further suggest favorable stability, half-life, and low hemolytic potential, supporting their suitability as therapeutic candidates. These findings align with prior studies highlighting the broad-spectrum antiviral activity of Griffithsin and validate the therapeutic promise of Brevinin-2 and CCL20. While this computational investigation lays the groundwork, further in vitro and in vivo validation and optimization of pharmacokinetics and delivery are necessary for clinical development. This study advances the rational design of peptide-based fusion inhibitors targeting MERS-CoV and provides valuable insights into antiviral strategies against emerging coronaviruses.
antibodies
2026-08-18 | Insights into the molecular recognition of the second PDZ domain of ZO1 by coronavirus Envelope-derived peptides.
The Envelope (E) protein, one of the structural proteins encoded by coronavirus (CoV) genome, is involved in multiple processes of the virus life cycle and directly related to the pathogenesis process. The C-terminus of E contains an important virulence factor, a PDZ domain binding motif (PBM), whose deletion or modification is sufficient to attenuate the virus. Notably, the PBM of E interacts with the second PDZ domain (PDZ2) of host Zonula Occludens 1 protein (ZO1), leading to delayed formation of tight junctions (TJs) and disruption of the respiratory epithelium. Although the binding reaction between ZO1-PDZ2 and E has been extensively studied since COVID-19 pandemic breakout, the structural determinants governing the binding process of ZO1-PDZ2 by E protein are still poorly understood. In this scenario, we performed a comparative study through a combination of experimental NMR and computational methods to structurally characterize the interaction occurring between ZO1-PDZ2 and three peptides mimicking the C-terminal PBM of E protein from SARS-CoV (now SARS-CoV-1), SARS-CoV-2, and MERS-CoV. Our results could provide the basis for the development of therapeutic strategies that may reduce cell damage and the morbidity and mortality associated with coronavirus infection.
2026-07-29 | Emerging zoonotic threats: HKU5-CoV-2 and the CBRNE approach to pandemic prevention.
The emergence of HKU5-CoV-2, a novel lineage in the Merbecovirus subgenus, represents a potential zoonotic threat with significant implications for global health. This bat-derived virus, which is phylogenetically similar to the Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 2, has demonstrated the ability to use the human angiotensin-converting enzyme 2 receptor to enter human cells. Although no human infections have been reported, its zoonotic potential raises the possibility of spillover events, which could lead to widespread transmission and, under certain conditions, pandemics. This study explores the virological characteristics, epidemiological risks, and clinical implications of HKU5-CoV-2, emphasizing its capacity to cross species barriers and cause severe respiratory diseases. To address the potential for a future pandemic, we propose a theoretical response framework based on the Chemical, Biological, Radiological, Nuclear, and Explosive approach traditionally employed for high-consequence biological threats. This strategy integrates early detection through advanced genomic surveillance, rapid containment measures, the development of targeted medical countermeasures, effective risk communication, and international collaboration. By leveraging lessons from previous coronavirus outbreaks, this framework aims to mitigate the impact of a potential HKU5-CoV-2 spillover and to ensure a coordinated and efficient global response. This study underscores the importance of preparedness in the face of emerging zoonotic viruses and provides a roadmap for managing future biological threats of pandemic potential.
2026-06-30 | Bioprocess Development of a Human Monoclonal Antibody against MERS-CoV: Analytical and Preclinical Studies.
Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a zoonotic virus first identified in 2012, responsible for severe respiratory illness and a high case fatality rate of approximately 35%. MERS-CoV is primarily transmitted from dromedary camels to humans, but human-to-human transmission, particularly in healthcare settings, has led to outbreaks beyond the Middle East, including a major epidemic in South Korea in 2015. Despite its significant public health threat and potential for future outbreaks, no approved vaccines or therapeutic agents are available for MERS-CoV. To address this urgent need, the Korea National Institute of Health (KNIH) developed therapeutic monoclonal antibodies derived from B cells of convalescent MERS patients. Among these, KNIH-88, a non-receptor-binding domain (non-RBD) S1-specific antibody, was selected for preclinical development. In this study, KNIH-88 was produced with high purity under controlled manufacturing conditions and extensively characterized for structural and physicochemical properties, including molecular weight, charge, hydrophobicity, and high molecular weight (HMW) profile. KNIH-88 demonstrated strong binding affinity to MERS-CoV Spike protein and potent neutralizing activity in vitro. To ensure stability and facilitate rapid deployment in outbreak scenarios, a lyophilized formulation of KNIH-88 was developed, maintaining structural integrity and biological activity under long-term storage. Collectively, these findings support KNIH-88 as a promising therapeutic antibody for MERS-CoV, combining potent antiviral efficacy, structural stability, and a formulation suitable for stockpiling and emergency use in endemic regions.
2026-04-01 | Evolutionary dynamics of Erinaceus coronavirus in Italy: spike protein adaptation and variable CD200 ortholog insertion
Introduction In 2013, a novel coronavirus (CoV) species was identified in European hedgehogs ( Erinaceus europaeus ) in Germany. Since then, only a limited number of studies reported the circulation of this virus, recognized as Erinaceus coronavirus (EriCoV), and demonstrated its evolutionary relationship with Middle East respiratory syndrome coronavirus (MERS-CoV). Given that MERS-CoV is one of the three zoonotic coronaviruses known to cause severe disease in humans, these findings raise concerns about the zoonotic potential of EriCoV strains. In a previous study conducted in Italy, eight complete EriCoV genomes were obtained from hedgehogs sampled in Northern Italy, revealing substantial genetic heterogeneity among circulating strains. Genome analyses also identified the insertion of a gene encoding the CD200 ortholog, containing a short region potentially involved in host immune modulation. The present study aimed to investigate the circulation and genetic diversity of coronaviruses in hedgehogs from different areas of Italy and to assess the occurrence and distribution of the CD200 ortholog insertion. Methods Complete EriCoV genomes were obtained from 35 hedgehogs using Next Generation Sequencing (NGS) by Ion Torrent machine. For an additional 20 animals, full genome sequences could not be generated; therefore, sequences were obtained by nested RT-PCR amplifying partial sequences of the RNA-dependent RNA polymerase (RdRp) gene and, when present, on the CD200 insertion. Phylogenetic analysis of sequences obtained were performed. Results Phylogenetic analysis revealed no clear geographic clustering, with sequences from Northern Italy interspersed with those from Central and Southern Italy. Analysis of the spike (S) protein identified 25 sites evolving under positive selection, three of which were located within the receptor-binding domain (RBD). The CD200 ortholog was confirmed in 15 complete genomes and in 5 additional samples by RT-PCR, collected from both Northern and Southern Italy. Discussion Overall, the study confirms that EriCoV related strains are found across the country. A CD200 insertion appears in both Northern and Southern regions, but it is not consistently present, indicating that this insertion is not fixed within the viral population. Sites found under positive selection in spike protein, including three in the receptor-binding domain, that may be relevant for host–virus interactions and merit further investigation in the context of cross-species transmission risks.
2026-03-23 | First evidence of zoonotic spillover of MERS-CoV into occupationally exposed populations in Somalia
Abstract Dromedary camels are the main reservoir for Middle East respiratory syndrome coronavirus (MERS-CoV), a re-emerging infectious disease with pandemic potential. Somalia harbours approximately 32% of dromedary camels globally. We investigated current and past MERS-CoV infections among occupationally-exposed workers in slaughterhouses, dairy farms, livestock markets and a quarantine station. Sera and nasopharyngeal/oropharyngeal swabs from 770 workers were analysed for MERS-CoV antibodies by Enzyme-Linked Immunosorbent Assay (ELISA) and virus neutralization and for viral RNA by Real Star® MERS-CoV Reverse Transcription Polymerase Chain Reaction (RT-PCR). One farm worker with no travel history in the Qardo district, Karkar region, Puntland was sero-positive by ELISA and virus neutralization, providing the first-ever evidence of zoonotic spillover of MERS-CoV to humans in Somalia. This finding highlights the need to strengthen MERS-CoV surveillance across Somalia, along with an urgent need to strengthen national laboratory capacity and integrate MERS into diagnostic algorithms to generate accurate and reliable infection data and studies to understand the socio-cultural and potential risk factors for MERS-CoV.
small molecules
2026-09-25 | 6-Substituted 7-Deazapurine Ribonucleosides Capable of Non-canonical Base Recognition as Inhibitors of Respiratory RNA Viruses
Abstract Most nucleoside antiviral analogues mimic canonical Watson−Crick base pairing to increase their likelihood of recognition and incorporation by replicative enzymes into a growing viral nucleic acid strand. Herein, we investigated whether non-canonical base recognition principles based on either shape complementarity or non-hydrogen bond interactions could also be exploited to generate novel small-molecule antivirals. Thus, the exogenous amino group of 7-deazaadenosine was systematically replaced with various 6-alkyl and 6-alkynyl substituents to assess their impact on antiviral activity against RNA respiratory viruses, including influenza A and B, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and respiratory syncytial virus (RSV). Sub-micromolar potency was observed for multiple compounds, with minimal cytotoxicity and inhibition of host DNA polymerases. Notably, the different modifications profoundly affected the antiviral spectrum, suggesting that despite lacking a hydrogen-bond donor, analogues with either 6-alkyl or 6-alkynyl substituents likely engage polymerases through distinct recognition mechanisms.
2026-09-24 | Solution structure, dynamics and fragment binding of unbound MERS-CoV nsp10
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) poses a significant public health threat, with a fatality rate of 37% and no approved therapeutics. Non-structural protein 10 (nsp10) is an essential cofactor that activates both the nsp14 3'-5' exoribonuclease (ExoN) activity required for RNA proofreading and the nsp16 2'-O-methyltransferase (2'-O-MTase) implicated in viral RNA cap formation. Despite its functional importance, the unbound structure and dynamics of MERS-CoV nsp10 in solution remain uncharacterised. Here we report a near-complete NMR backbone and sidechain assignment and characterise the solution structure and dynamics of the protein by NMR. In contrast to the folded α1 helix observed in crystal structures of coronavirus nsp10, we find that this region is intrinsically disordered in solution, with residues 10-22 undetectable under standard conditions and further evidenced by pH titration, temperature-dependent NMR, and CLEANEX-PM experiments. Analysis of NOE contacts confirmed that the core adopts the conserved coronavirus nsp10 fold, consistent with the AlphaFold-predicted structure. 15N backbone relaxation measurements indicated a rigid, well-ordered core with only localised flexibility, despite a relatively low proportion of secondary structure elements, and CPMG and CEST experiments detected no conformational exchange on the μs-ms timescale. Building on this structural and dynamic characterisation, we explored the ligandability of nsp10 by 19F NMR fragment screening. Screening of a 463-compound library identified 23 initial hits (4.97% hit rate), of which 20 were confirmed by 15N SOFAST-HMQC and eight gave quantifiable affinities by MST (Kd 0.5-6.9 mM), the remainder being too weak for reliable determination. Chemical shift perturbations clustered near functional surfaces of the folded core, indicating that MERS-CoV nsp10 is ligandable and providing chemical starting points for antiviral development.
2026-09-15 | Mutation-Aware Machine Learning Framework for Predicting Binding Affinity of Nirmatrelvir Analogs Targeting Coronavirus Main Proteases.
The emergence of resistance-associated mutations in coronavirus main protease (Mpro) poses a significant challenge to the development of broad-spectrum antiviral therapeutics. In this study, we improved and accelerated a mutation-aware machine learning (ML) framework to predict the binding score of Nirmatrelvir analogue ligands against wild-type and mutant MERS-CoV Mpro. A library of 15,889 Nirmatrelvir derivatives generated through systematic scaffold modification was docked against the wild-type and five variants of the Mpro, producing a total of 95,334 structural and docking score datasets of these protein-ligand complexes. During the ML model development phase, ligand effects were learned from RDKit molecular descriptors and graph-based representations, and the mutation-induced effects were captured through delta-encoded physicochemical properties (hydrophobicity, charge, aromaticity, and polarity) of the active-site residues. Among the evaluated models, the CatBoost regressor tree-based algorithm achieved the lowest mean absolute error (MAE) value of 0.23 Kcal/mol and an R2 of 0.87. Further improvement was achieved by creating a weighted ensemble model combining the CatBoost regressor, XGBoost and LightGBM regressor, resulting in a prediction accuracy with a MAE of 0.19 Kcal/mol and an R2 of 0.90 relative to docking scores. Model robustness was further evaluated through random-, ligand group- and scaffold group- K-fold cross-validation along with their Y-randomization. Moreover, the models were also tested with a new set of 1000 structurally diverse compounds. SHAP analysis was conducted, which identified 20 molecular descriptors critical for accurate predictions. The ensemble model accurately predicted the binding affinities of Nirmatrelvir and its four analogues (E1-E4), reproducing the experimental pIC50 trend and correctly identifying the most potent inhibitors. The ensemble model also showed consistent performance across all MERS-CoV Mpro variants, S147Y, S142G, L144A, S142G/S147Y, and S142G/L144A/S147Y, demonstrating its potential for rapidly discovering mutation-resistant antiviral drugs.
2026-09-02 | mTOR Signaling as a Central Regulator of Coronavirus Replication: Mechanistic Insights and Translational Opportunities
Coronaviruses comprise a diverse group of enveloped, positive-sense single-stranded RNA viruses capable of causing high morbidity in humans and livestock. The repeated emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 underscores the critical need for broad-spectrum countermeasures. Mounting evidence demonstrates that successful coronavirus infection depends on the manipulation of host cellular pathways governing translation, metabolism, autophagy, and survival. The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that functions via the mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2) to integrate extracellular and intracellular signals. Rather than remaining passive metabolic bystanders, coronaviruses actively exploit and rewrite host PI3K/Akt/mTOR networks to facilitate structural translation, assemble double-membrane replication organelles, suppress autophagic clearance, and reprogram protective innate and adaptive immune landscapes. This review provides a comprehensive synthesis of the molecular mechanisms dictating coronavirus–mTOR interactions across human pathogens and high-impact veterinary models. We detail the clinical consequences of dysregulated mTOR signaling—including immunometabolic perturbations, long-term metabolic memory, and tissue-specific complications—and evaluate the therapeutic potential of allosteric rapalogs, dual ATP-competitive inhibitors, and natural compounds as host-directed platforms designed to complement conventional antiviral regimens and enhance global pandemic preparedness.
2026-08-31 | Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro.
This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf, exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.
vaccines
2026-09-02 | An Engineered HR1-Stem Helix-HR2 Trimeric Platform for Developing Broad-Spectrum Coronavirus Vaccines.
The rapid spread of immune-evasive viral variants, exemplified by SARS-CoV-2, highlights the urgent need for broad-spectrum coronavirus vaccines. Although multimeric display of the receptor-binding domain (RBD) using exogenous scaffolds improve immune responses, such approaches may elicit off-target immune responses against the scaffolds themselves and remain limited by rapid RBD antigenic drift. Here, we report the rational design of a self-assembling trimeric subunit vaccine, termed RBD-heptad repeat 1 (HR1)-stem helix (SH)-heptad repeat 2 (HR2) (RHS), which integrates the JN.1 RBD with a highly conserved SH epitope from SARS-CoV-2 within a native HR1-HR2 trimeric scaffold via optimized linkers. RHS exhibits high structural stability, efficient trimerization, and enhanced antigen presentation. In mice, RHS elicits robust humoral and cellular immune responses, including potent cross- neutralizing antibodies against diverse SARS-CoV-2 variants and pan-betacoronavirus SH-specific antibodies. In K18-hACE2 mice, RHS confers strong protection against both antigen-matched and antigen-mismatched Omicron variants, while intranasal immunization induces potent mucosal IgA and IgG responses. Furthermore, the modular RHS platform is readily adaptable to antigens from SARS-CoV and MERS-CoV, underscoring its versatility for pan-coronavirus vaccine development. Together, these findings establish RHS as a generalizable strategy for overcoming viral immune evasion and advancing next-generation vaccine design.
2026-08-26 | Plant-Produced Vaccines for Protection from Human and Veterinary Coronaviruses.
Coronaviruses are responsible for numerous diseases causing substantial morbidity and mortality to both humans and animals. In particular, they have caused three significant outbreaks in humans including severe acute respiratory syndrome 1 (SARS-CoV-1), Middle East respiratory syndrome (MERS-CoV), and, most recently, the severe acute respiratory syndrome 2 (SARS-CoV-2) pandemic. Two relevant veterinary diseases are porcine transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV), which cause severe losses in the pork industry. While efficacious vaccines were developed in an unprecedented timeframe for COVID-19, vaccines have not been commercialized for other human coronaviruses and vaccines against animal coronaviruses have limited efficacy and logistical challenges in administration. There is a clear need for more efficacious vaccines with simpler methods of delivery and administration for both human and veterinary use. The production of subunit vaccines in plant systems holds great promise in addressing the current challenges and facilitate the preparation for future potential outbreaks and new viruses. This review will summarize the state of development of vaccines in plant systems including tobacco, rice, maize, and others.
2026-08-20 | Protective pan-betacoronavirus neutralizing antibodies by vaccination.
The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo . Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness. Epitope-focused S2 stem-helix nanoparticle immunogens elicit protective broadly neutralizing antibodies (bnAbs) against diverse betacoronaviruses in non-human primates, establishing a framework for development of pan-betacoronavirus vaccines.
2026-07-22 | Intranasal gold nanoparticle-antigen induces mucosal and systemic immunity against β-coronaviruses
The continued emergence of diverse beta-coronaviruses (β-CoVs) from animal reservoirs underscores the urgent need for broad-spectrum mucosal vaccines, yet their development is hindered by physiological barriers, rapid antigen clearance, and suboptimal multivalent display strategies. To address this, we intranasally immunized BALB/c mice ( n = 3 or 4 per group) with 5 or 15 nm gold nanoparticles (AuNPs) displaying the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD, 5 μg per mouse) and adjuvanted with the STING agonist cGAMP (20 μg per mouse). Guided by the serotyping of STING agonist-elicited neutralizing responses, we generated AuNP-Mix co-displaying six representative β-CoV RBDs for comparative immunological evaluation against single-RBD AuNP formulations. Antigen delivery, pulmonary retention, mucosal and systemic immune responses were evaluated via in vivo imaging, enzyme-linked immunosorbent assays, pseudovirus neutralization assays, flow cytometry, immunofluorescence, and challenge studies. We demonstrated that 5 nm AuNP-RBD adjuvanted with cGAMP exhibited superior mucosal penetration and lung retention, induced robust local and systemic immunity, and elicited cross-neutralizing antibodies against SARS-CoV-2 variants, SARS-CoV, and SARS-related coronaviruses. Intranasal immunization with AuNP-Mix elicited broader mucosal/systemic immune responses than those achieved with simple RBD mixtures, as demonstrated by its potent neutralizing activity against SARS-CoV-2 variants, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and divergent MERS-like viruses. These findings establish AuNP-based mosaic display as a versatile platform for next-generation mucosal vaccines.
2026-07-01 | Minor differences in the untranslated regions of measles vector additional transcription units are reflected by differential immunogenicity of encoded MERS-CoV Spike antigen.
The recombinant measles virus (MeV) is among those vaccine platform technologies, which are tested for the fast generation of effective vaccines against other pathogens, such as emerging virus diseases. Different live-attenuated vaccine strains have become available as backbones, with few differences. Here, we analyze how minor differences of recombinant Moraten (MVvac2) or Schwarz (MVSchw) constructs have an impact on the performance of respective derived Middle East respiratory syndrome (MERS) vaccine candidates. MVvac2 or MVSchw viruses, both encoding the Spike glycoprotein (S) of the MERS-coronavirus (MERS-CoV) in an additional transcription unit (ATU) between the hemagglutinin gene and the polymerase gene L cassette, were tested. Both robustly expressed the additional gene. However, approximately twofold to threefold higher amounts of S proteins were observed in cells infected by the MVSchw-MERS-S(H) virus, correlating with the same relative ratio of S mRNA found in these cells. Exchange of the short genomic 3' UTR ATU sequence in MVvac2 against the sequence in MVSchw enhanced gene expression by about the same factor and demonstrates causality. MeV-susceptible IFNAR-/--CD46Ge mice vaccinated with either candidate reveal that higher relative S antigen expression by MVSchw-MERS-S(H) tended toward induction of higher specific antibody titers, but lower numbers of S antigen-specific T cells. In subsequent challenge experiments, both candidates were effective. Thus, minor differences in the genetic composition of recombinant MeV's ATU may modulate the gene expression pattern of additionally encoded proteins that are reflected by changes in the respective immunogenicities, but which were not decisive for protection in the chosen disease model. In case of emerging or re-emerging infections, vaccine platform technologies are needed to rapidly develop effective vaccines to aid public healthcare in pandemics. Besides mRNA vaccines, also viral platform technologies, that is, the adenovirus-derived vaccines Vaxzevria and JCOVDEN, have proven to be of immense value during the COVID-19 pandemic. For future pandemics, it is crucial to understand the factors in vector design that modulate immunogenicity. This knowledge allows the tailoring of vaccine vectors to fit specific target product profiles, for example, to build vectors which trigger an accentuated T cell or, alternatively, antibody response against an antigen of interest. Our study using the live-attenuated measles vaccine backbone as a promising example is therefore crucial in demonstrating that very minor differences in the vaccine backbone can alter the antigen expression profile of the vector-antigen system and impact the relative induction of T-cell or antibody responses against the added target antigen.
other
2026-08-13 | Genotype to phenotype consequences in MERS-CoV
Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia in 2012 and has a reported mortality rate of 36%, making it the most pathogenic human coronavirus known. Dromedary camels are the major reservoir of MERS-CoV, with regular spillover into humans presenting a significant public health risk. Human-to-human transmission has been confirmed between close contacts in healthcare settings and those residing in the same household. Currently, there are no specific medical countermeasures available to treat MERS-CoV infection. Much of the MERS-CoV research to date has focussed on the EMC/2012 reference strain, which is phylogenetically classified as clade A. However, clade A viruses have been considered extinct since 2015, while the majority of MERS-CoV strains causing human infections belong to clade B, lineage 5. It was hypothesised that naturally occurring Spike mutations identified in human MERS-CoV infections would result in phenotypic differences in virus entry and neutralisation. It was also hypothesised that contemporary MERS-CoV strains would replicate and adapt differently in humans relative to EMC/2012. Therefore, it is important to understand the genotype to phenotype consequences in contemporary MERS-CoV strains to increase knowledge surrounding human infections. This will also facilitate a more effective response to virus adaptation and improve pandemic preparedness. Here, two tools were developed to study contemporary MERS-CoV: a lentiviral pseudotyping system and a yeast-based reverse genetics system. Pseudotypes were used to characterise naturally occurring Spike mutations identified in human MERS-CoV sequences. Split GFP cell-cell fusion assays demonstrated that I529T, E536K, L745F and Ins885 improved MERS-CoV entry. While microneutralisation assays demonstrated that L411F, T424I, L506F, L745F and T746K increased resistance to neutralisation by pooled patient sera. A recombinant MERS-CoV (rMERS-CoV) full-length infectious clone carrying a representative clade B, lineage 5 sequence was generated via reverse genetics. rMERS-CoV was subsequently used to study infectivity, replication and genetic stability of contemporary strains in human cells. Replication of rMERS-CoV in primary human nasal epithelial cells was found to be improved relative to EMC/2012. Additionally, the host response to rMERS-CoV infection was investigated in Calu-3 cells, whereby significantly upregulated genes included those associated with the innate immune response and cellular stress response elements. Ultimately, the evidence presented here indicates contemporary MERS-CoV strains may be becoming more infectious in humans, while also carrying mutations that facilitate immune evasion. Crucially, contemporary MERS-CoV replicated to significantly higher titres than EMC/2012 in an in vitro model of the upper respiratory tract. These findings highlight the importance of continued surveillance and study of contemporary strains to manage the pandemic threat posed by MERS-CoV. Furthermore, in addition to being used alongside surveillance systems, the tools developed in this thesis could be used in the development of therapeutics to treat MERS disease.
2026-04-22 | Comparative genomics identifies small interfering RNA with activity against all five human betacoronaviruses.
BACKGROUND: The Orthocoronavirinae virus subfamily (CoV) poses a continuous global health threat. Seven CoV species are known to infect humans and additional animal CoVs with potential for human spillover have been identified. Currently, antiviral drugs are available only against SARS-CoV-2, underscoring the need for broad-spectrum antivirals. Targeting the viral RNA genome with small interfering RNAs (siRNAs) induces its degradation by endogenous nucleases and represents an effective strategy to inhibit CoV replication. Previous studies have demonstrated the efficacy and feasibility of this approach against individual CoV species. However, its potential to serve as a broad-spectrum antiviral strategy effective across multiple members of the CoV subfamily has not been systematically explored. METHODS: The conservation of all potential siRNA target sites within the CoV genome (n ≈ 30,000) was analyzed using a custom database comprising 250,000 full-length genome sequences from 44 CoV species isolated from diverse mammalian and avian hosts. Antiviral activity of selected siRNA candidates was screened using a replication-competent recombinant SARS-CoV-2 expressing green fluorescent protein. The effect of target site mismatches was assessed using luciferase reporters, and cross-species antiviral activity was evaluated against six representative wild-type CoVs. Cellular toxicity was investigated by monitoring cell death, confluence, metabolic activity, and in silico prediction of siRNA off-target activity. RESULTS: Conservation of potential siRNA target sites correlated with the evolutionary distance between CoV species. Several genomic regions were conserved across different CoV subgenera and genera, but no site was universally preserved across all 44 analyzed species. The antiviral activity and tolerability of 347 siRNAs targeting the most promising sites were evaluated in multiple screening rounds. Following optimization of siRNA design and chemistry, we identified a lead candidate, si117m, which displayed high tolerability and potent silencing activity at picomolar concentrations against target sites of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43 and HCoV-HKU1. CONCLUSIONS: Our study demonstrates the potential of comparative genomics for developing broad-spectrum antiviral siRNAs. We identified a lead siRNA, si117m, which combines a favorable safety profile with cross-species activity against five human CoVs, supporting its potential for clinical translation and future pandemic preparedness.
2026-04-10 | QStrain: an interactive platform for viral genome analysis and nucleic acid therapeutic design
Abstract Background QStrain is an integrated resource platform designed to facilitate viral genome analysis and the rational design of nucleic acid therapeutics. Results The system integrates reference-guided multiple sequence alignment of high-risk viral pathogens, including Severe Acute Respiratory Syndrome Coronavirus 2, Lassa virus, Severe Fever with Thrombocytopenia Syndrome virus, Middle East Respiratory Syndrome Coronavirus, Influenza A virus subtype H5N1 and H7N9, Nipah virus, Respiratory Syncytial Virus, and Dengue virus, with a growing database of viral genomes. QStrain provides versatile visualization modules such as frequency profiles, conservation scores, RNA expression patterns, and phylogenetic trees to enhance the interpretation of viral sequence variation. By identifying highly conserved genomic regions, QStrain supports the prediction of candidate therapeutic targets and enables the automated design of small interfering RNA (siRNA) and antisense oligonucleotides (ASOs). Additional features include off-target searching and 2D structure viewing for comprehensive assessment of therapeutic potential. Conclusions Ultimately, QStrain ( https://qstrain.sookmyung.ac.kr ) provides a critical, user-friendly framework to accelerate the design pipeline of nucleic acid-based therapies, enhancing preparedness against current and future viral outbreaks.
2026-02-28 | Unveiling the epitope repertoires and protective roles of MERS-CoV-specific T cells in mice.
Since its initial emergence in 2012, MERS-CoV has remained endemic and a global health threat. While accessory proteins (ORFs) are known for immune evasion, their role in adaptive immunity is unexplored. This study systematically investigated T cell responses against MERS-CoV ORFs. We mapped epitope repertoires targeting structural proteins and ORFs in C57BL/6 and BALB/c mice, revealing that ORFs potently induced virus-specific T cells. Notably, ORF5 induced the dominant CD8+ T cell responses in BALB/c mice. Further analysis revealed that ORF4b208-specific CD4+ and ORF5167-specific CD8+ T cells in the respiratory tract exhibited polyfunctional cytokine profiles, high antigen sensitivity, and potent in vivo cytotoxicity. These specific T cells played protective roles during MERS-CoV infection by promoting viral clearance. Collectively, this study identified MERS-CoV-specific T cell epitopes and elucidated the roles of ORF4b- and ORF5-specific T cells, enhancing our understanding of anti-MERS-CoV T cell responses and advancing vaccine design strategies against MERS-CoV.
2025-12-10 | MERS-CoV RBD-mRNA Presents Better Immunogenicity and Protection than the Spike-mRNA.
Pathogenic Middle East respiratory syndrome CoV (MERS-CoV), first identified in Saudi Arabia in 2012, continues to pose a threat to public health. The trimeric spike (S) protein of MERS-CoV binds to the cellular receptor through the receptor-binding domain (RBD) in the S1 subunit to initiate virus entry and infection. Therefore, both the S protein and its RBD are targets for the development of MERS-CoV vaccines. Nevertheless, a direct comparison of the immune efficiency of S- and RBD-based MERS-CoV vaccines has not been made. Here, we compared two mRNA vaccines, respectively, targeting the S (S-mRNA) and RBD (RBD-mRNA) of MERS-CoV for their durable immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Both mRNAs encapsulated with lipid nanoparticles (LNPs) maintained strong stability at various temperatures during the detection period. LNP-encapsulated RBD-mRNA elicited significantly higher and more durable antibodies than LNP-encapsulated S-mRNA, maintaining stronger and broadly neutralizing activity against the MERS-CoV original strain, as well as multiple variants containing key mutations within the RBD region. Importantly, RBD-mRNA provided durable protective efficacy against MERS-CoV infection in middle-aged mice, and this protection was associated positively with serum neutralizing antibody titers. Overall, this study identifies RBD-mRNA as an effective vaccine against MERS-CoV, with great potential for further development.
proteins
2026-09-20 | Reduced DPP4 Binding Confers Resistance to Soluble DPP4 While Preserving MERS-CoV Entry into Cells Expressing High Levels of DPP4
ABSTRACT The Middle East respiratory syndrome coronavirus uses DPP4/CD26 as receptor for cell entry. Soluble recombinant DPP4 can block MERS-CoV infection in cell culture and in animal models and might hold promise as antiviral. Furthermore, endogenous soluble DPP4 in plasma might reduce MERS-CoV dissemination in infected individuals. Therefore, we addressed whether and how MERS-CoV can acquire resistance against soluble DPP4 (sDPP4), employing a vesicular stomatitis virus (VSV) encoding the MERS-CoV spike (S) protein (VSV-MERS-S). Passaging of VSV-MERS-S in the presence of sDPP4 selected for viral variants with mutations L507I and L507H in the receptor binding domain (RBD) of the S protein. These mutations reduced sDPP4 binding, were compatible with robust entry into cell lines expressing high levels of DPP4 and conferred sDPP4 resistance. In contrast, entry into cell lines expressing low levels of DPP4 was reduced. Furthermore, polymorphisms L507F/R/P, which were detected in MERS-CoV sequences from patients, exhibited an even more pronounced phenotype, with L507R and L507P conferring complete sDPP4 resistance. Collectively, our results show that naturally occurring polymorphisms in the MERS-CoV S protein can confer sDPP4 resistance by reducing sDPP4 binding but might still be compatible with robust viral spread in cells and tissues expressing high levels of DPP4. IMPORTANCE DPP4 is the cellular receptor used by MERS-CoV for entry into target cells. A soluble form of DPP4 (sDPP4) blocks MERS-CoV infection and has been proposed as a potential antiviral. Here, using surrogate systems, we show that MERS-CoV can acquire resistance to sDPP4 through spike protein mutations that reduce DPP4 binding. These mutations remain compatible with efficient entry into cells expressing high levels of DPP4 and were also identified in patient-derived MERS-CoV. Our findings suggest that MERS-CoV can balance receptor engagement with resistance to a soluble receptor decoy, with implications for antiviral strategies targeting virus-receptor interactions.
2026-06-23 | Broadly Protective Antibody-Like Vaccines Against Highly Pathogenic Coronaviruses.
SARS-CoV-2 and MERS-CoV are highly pathogenic and contagious coronaviruses. Despite intensive vaccination, SARS-CoV-2 continues to spread, and no FDA-approved vaccines exist for MERS-CoV; thus, more effective and safer vaccine options are needed. The receptor-binding domain (RBD) of coronaviruses is a primary target of neutralizing antibodies (nAbs); therefore, we generated three bivalent IgG1 Fc-fusion vaccines (BiVaxs) combining SARS-CoV-2 and MERS-CoV RBDs. The BiVaxFc-Native vaccine comprises omicron's-RBDSARS-CoV-2 fused to the native Fc C-terminus and RBDMERS-CoV to the N-terminus. The BiVaxFc-Reverse vaccine has a native Fc, yet RBDMERS-CoV was fused to the C-terminus, and the omicron's-RBDSARS-CoV-2 to the N-terminus. The third was BiVaxFc-FcRn, which is similar to BiVaxFc-Native, although it contains MST-HN Fc mutations (M252Y/S254T/T256E-H433K/N434F) to enhance neonatal Fc receptor (FcRn) binding on antigen-presenting cells (APCs). In mice, BiVaxFc-FcRn showed significantly higher immunogenicity than the other two forms. It induced robust IgG and nAb responses against RBDMERS-CoV after two doses and moderate responses omicron's-RBDSARS-CoV-2 after the third dose. Remarkably, it also generated strong cross-reactive antibodies against SARS-CoV-1. These findings suggest that RBDMERS-CoV is more immunogenic than omicron's-RBDSARS-CoV-2, and that BiVaxFc-FcRn has a high potential for further development as a broad-spectrum vaccine platform to prevent infection with the targeted coronaviruses as well as future emerging viruses.
2026-06-12 | Cleavage of TOM1 by the SARS-CoV-2 main protease NSP5 prevents autophagic degradation of viral envelope.
Autophagy plays a critical role in viral replication and the regulation of host immune responses. Although the TOM1-TOLLIP complex has been implicated in immune signaling, cargo trafficking, and endocytosis, its role in viral replication has not been defined. Here, we demonstrate that the SARS-CoV-2 main protease (NSP5) cleaves TOM1 at residue Q354 through its protease activity. This cleavage is also observed with the main proteases of SARS-CoV and MERS-CoV. Importantly, TOM1 overexpression suppresses SARS-CoV-2 replication in HEK293T-hACE2 and Vero cells, while TOM1 knockout via CRISPR-Cas9 significantly enhances viral propagation, indicating that TOM1 functions as a novel restriction factor against SARS-CoV-2 infection. Moreover, various TOM1 orthologs from diverse species, including cattle, bats, monkeys, mice, and ducks, show similar restriction to SARS-CoV-2, but they all are antagonized by NSP5 cleavage. Mechanistically, we found that TOM1 recruits the autophagy receptor TOLLIP to target SARS-CoV-2 envelope (E) protein for autophagic degradation, thereby limiting viral replication. These findings highlight the importance of the TOM1-TOLLIP complex in host defense and discover that SARS-CoV-2 exploits a conserved NSP5-mediated TOM1 cleavage mechanism to evade host antiviral defenses.IMPORTANCEViruses must overcome the body's natural defenses in order to replicate and spread. One important cellular defense mechanism is autophagy, a process that helps cells remove harmful proteins and pathogens. In this study, we discovered that a host protein called TOM1 acts as a restriction factor that helps limit the replication of SARS-CoV-2, the virus responsible for COVID-19. TOM1 works together with another protein, TOLLIP, to direct envelope proteins to the cell's degradation system, thereby reducing viral replication. However, SARS-CoV-2 has evolved a strategy to counter this defense. The viral main protease (NSP5) cleaves TOM1, disabling its antiviral activity. This mechanism is conserved among several coronaviruses, including SARS-CoV and MERS-CoV. Our findings reveal a previously unrecognized antiviral role of the TOM1-TOLLIP complex and demonstrate how coronaviruses evade this host defense, providing new insight into virus-host interactions and potential targets for antiviral therapies.
2026-05-27 | Modulation of Host Innate Immune Response by Highly Pathogenic Human Coronaviruses during Viral Infection.
Highly pathogenic human coronaviruses, including SARS-CoV, SARS-CoV-2, and MERS-CoV have emerged as significant public health threats due to their ability to cause widespread outbreaks and pandemics. These viruses induce dysregulated inflammatory responses, typified by cytokine storms that drive extensive tissue damage in pulmonary and extrapulmonary systems, leading to acute respiratory distress syndrome (ARDS) and multi-organ failure. These pathological outcomes are driven by sophisticated mechanisms that manipulate host immune pathways and evade innate and adaptive immune surveillance. The innate immune system plays a pivotal role in the early detection and control of viral infections through mechanisms such as cytoplasmic RNA sensors, Toll-like receptors, interferon signaling, and inflammasome activation. However, these coronaviruses effectively exploit and subvert these processes, suppressing antiviral defenses while amplifying inflammatory cascades. This review delineates the molecular and cellular strategies employed by these pathogens to evade immune recognition and exacerbate immune-mediated tissue injury. Understanding these processes is fundamental for guiding the development of targeted antiviral interventions, immunomodulatory therapeutics, and robust strategies to mitigate the impact of future coronavirus pandemics.
2026-05-05 | Targeting Middle East Respiratory Syndrome Coronavirus Spike Fusion Machinery With Antiviral Peptides: In Silico Exploration of the Heptad Repeat 2 Domain.
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) remains a significant global health threat, necessitating the development of effective antiviral therapeutics. Targeting the heptad repeat 2 (HR2) domain of the MERS-CoV spike protein offers a promising strategy to inhibit viral fusion and entry into host cells. This study investigates a panel of antiviral peptides (AVPs), focusing on Griffithsin, Brevinin-2, and CCL20, to evaluate their potential as fusion inhibitors against the HR2 domain. Employing comprehensive computational approaches, including molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy calculations, we characterized the peptide-protein interactions and stability of these AVPs in complex with HR2. Our results demonstrate that Griffithsin, Brevinin-2, and CCL20 exhibit stronger binding affinities (- 213.69, -168.83, and -165.17 kcal/mol, respectively) compared to the standard inhibitor Peptide-6 (- 49.73 kcal/mol). MD simulations reveal stable complexes and indicate disruption of critical hydrogen bonds in the Ile1255-Gln1271 region of HR2, essential for six-helix bundle formation and viral fusion. Physicochemical analyses further suggest favorable stability, half-life, and low hemolytic potential, supporting their suitability as therapeutic candidates. These findings align with prior studies highlighting the broad-spectrum antiviral activity of Griffithsin and validate the therapeutic promise of Brevinin-2 and CCL20. While this computational investigation lays the groundwork, further in vitro and in vivo validation and optimization of pharmacokinetics and delivery are necessary for clinical development. This study advances the rational design of peptide-based fusion inhibitors targeting MERS-CoV and provides valuable insights into antiviral strategies against emerging coronaviruses.
antibodies
2026-08-18 | Insights into the molecular recognition of the second PDZ domain of ZO1 by coronavirus Envelope-derived peptides.
The Envelope (E) protein, one of the structural proteins encoded by coronavirus (CoV) genome, is involved in multiple processes of the virus life cycle and directly related to the pathogenesis process. The C-terminus of E contains an important virulence factor, a PDZ domain binding motif (PBM), whose deletion or modification is sufficient to attenuate the virus. Notably, the PBM of E interacts with the second PDZ domain (PDZ2) of host Zonula Occludens 1 protein (ZO1), leading to delayed formation of tight junctions (TJs) and disruption of the respiratory epithelium. Although the binding reaction between ZO1-PDZ2 and E has been extensively studied since COVID-19 pandemic breakout, the structural determinants governing the binding process of ZO1-PDZ2 by E protein are still poorly understood. In this scenario, we performed a comparative study through a combination of experimental NMR and computational methods to structurally characterize the interaction occurring between ZO1-PDZ2 and three peptides mimicking the C-terminal PBM of E protein from SARS-CoV (now SARS-CoV-1), SARS-CoV-2, and MERS-CoV. Our results could provide the basis for the development of therapeutic strategies that may reduce cell damage and the morbidity and mortality associated with coronavirus infection.
2026-07-29 | Emerging zoonotic threats: HKU5-CoV-2 and the CBRNE approach to pandemic prevention.
The emergence of HKU5-CoV-2, a novel lineage in the Merbecovirus subgenus, represents a potential zoonotic threat with significant implications for global health. This bat-derived virus, which is phylogenetically similar to the Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 2, has demonstrated the ability to use the human angiotensin-converting enzyme 2 receptor to enter human cells. Although no human infections have been reported, its zoonotic potential raises the possibility of spillover events, which could lead to widespread transmission and, under certain conditions, pandemics. This study explores the virological characteristics, epidemiological risks, and clinical implications of HKU5-CoV-2, emphasizing its capacity to cross species barriers and cause severe respiratory diseases. To address the potential for a future pandemic, we propose a theoretical response framework based on the Chemical, Biological, Radiological, Nuclear, and Explosive approach traditionally employed for high-consequence biological threats. This strategy integrates early detection through advanced genomic surveillance, rapid containment measures, the development of targeted medical countermeasures, effective risk communication, and international collaboration. By leveraging lessons from previous coronavirus outbreaks, this framework aims to mitigate the impact of a potential HKU5-CoV-2 spillover and to ensure a coordinated and efficient global response. This study underscores the importance of preparedness in the face of emerging zoonotic viruses and provides a roadmap for managing future biological threats of pandemic potential.
2026-06-30 | Bioprocess Development of a Human Monoclonal Antibody against MERS-CoV: Analytical and Preclinical Studies.
Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a zoonotic virus first identified in 2012, responsible for severe respiratory illness and a high case fatality rate of approximately 35%. MERS-CoV is primarily transmitted from dromedary camels to humans, but human-to-human transmission, particularly in healthcare settings, has led to outbreaks beyond the Middle East, including a major epidemic in South Korea in 2015. Despite its significant public health threat and potential for future outbreaks, no approved vaccines or therapeutic agents are available for MERS-CoV. To address this urgent need, the Korea National Institute of Health (KNIH) developed therapeutic monoclonal antibodies derived from B cells of convalescent MERS patients. Among these, KNIH-88, a non-receptor-binding domain (non-RBD) S1-specific antibody, was selected for preclinical development. In this study, KNIH-88 was produced with high purity under controlled manufacturing conditions and extensively characterized for structural and physicochemical properties, including molecular weight, charge, hydrophobicity, and high molecular weight (HMW) profile. KNIH-88 demonstrated strong binding affinity to MERS-CoV Spike protein and potent neutralizing activity in vitro. To ensure stability and facilitate rapid deployment in outbreak scenarios, a lyophilized formulation of KNIH-88 was developed, maintaining structural integrity and biological activity under long-term storage. Collectively, these findings support KNIH-88 as a promising therapeutic antibody for MERS-CoV, combining potent antiviral efficacy, structural stability, and a formulation suitable for stockpiling and emergency use in endemic regions.
2026-04-01 | Evolutionary dynamics of Erinaceus coronavirus in Italy: spike protein adaptation and variable CD200 ortholog insertion
Introduction In 2013, a novel coronavirus (CoV) species was identified in European hedgehogs ( Erinaceus europaeus ) in Germany. Since then, only a limited number of studies reported the circulation of this virus, recognized as Erinaceus coronavirus (EriCoV), and demonstrated its evolutionary relationship with Middle East respiratory syndrome coronavirus (MERS-CoV). Given that MERS-CoV is one of the three zoonotic coronaviruses known to cause severe disease in humans, these findings raise concerns about the zoonotic potential of EriCoV strains. In a previous study conducted in Italy, eight complete EriCoV genomes were obtained from hedgehogs sampled in Northern Italy, revealing substantial genetic heterogeneity among circulating strains. Genome analyses also identified the insertion of a gene encoding the CD200 ortholog, containing a short region potentially involved in host immune modulation. The present study aimed to investigate the circulation and genetic diversity of coronaviruses in hedgehogs from different areas of Italy and to assess the occurrence and distribution of the CD200 ortholog insertion. Methods Complete EriCoV genomes were obtained from 35 hedgehogs using Next Generation Sequencing (NGS) by Ion Torrent machine. For an additional 20 animals, full genome sequences could not be generated; therefore, sequences were obtained by nested RT-PCR amplifying partial sequences of the RNA-dependent RNA polymerase (RdRp) gene and, when present, on the CD200 insertion. Phylogenetic analysis of sequences obtained were performed. Results Phylogenetic analysis revealed no clear geographic clustering, with sequences from Northern Italy interspersed with those from Central and Southern Italy. Analysis of the spike (S) protein identified 25 sites evolving under positive selection, three of which were located within the receptor-binding domain (RBD). The CD200 ortholog was confirmed in 15 complete genomes and in 5 additional samples by RT-PCR, collected from both Northern and Southern Italy. Discussion Overall, the study confirms that EriCoV related strains are found across the country. A CD200 insertion appears in both Northern and Southern regions, but it is not consistently present, indicating that this insertion is not fixed within the viral population. Sites found under positive selection in spike protein, including three in the receptor-binding domain, that may be relevant for host–virus interactions and merit further investigation in the context of cross-species transmission risks.
2026-03-23 | First evidence of zoonotic spillover of MERS-CoV into occupationally exposed populations in Somalia
Abstract Dromedary camels are the main reservoir for Middle East respiratory syndrome coronavirus (MERS-CoV), a re-emerging infectious disease with pandemic potential. Somalia harbours approximately 32% of dromedary camels globally. We investigated current and past MERS-CoV infections among occupationally-exposed workers in slaughterhouses, dairy farms, livestock markets and a quarantine station. Sera and nasopharyngeal/oropharyngeal swabs from 770 workers were analysed for MERS-CoV antibodies by Enzyme-Linked Immunosorbent Assay (ELISA) and virus neutralization and for viral RNA by Real Star® MERS-CoV Reverse Transcription Polymerase Chain Reaction (RT-PCR). One farm worker with no travel history in the Qardo district, Karkar region, Puntland was sero-positive by ELISA and virus neutralization, providing the first-ever evidence of zoonotic spillover of MERS-CoV to humans in Somalia. This finding highlights the need to strengthen MERS-CoV surveillance across Somalia, along with an urgent need to strengthen national laboratory capacity and integrate MERS into diagnostic algorithms to generate accurate and reliable infection data and studies to understand the socio-cultural and potential risk factors for MERS-CoV.
small molecules
2026-09-25 | 6-Substituted 7-Deazapurine Ribonucleosides Capable of Non-canonical Base Recognition as Inhibitors of Respiratory RNA Viruses
Abstract Most nucleoside antiviral analogues mimic canonical Watson−Crick base pairing to increase their likelihood of recognition and incorporation by replicative enzymes into a growing viral nucleic acid strand. Herein, we investigated whether non-canonical base recognition principles based on either shape complementarity or non-hydrogen bond interactions could also be exploited to generate novel small-molecule antivirals. Thus, the exogenous amino group of 7-deazaadenosine was systematically replaced with various 6-alkyl and 6-alkynyl substituents to assess their impact on antiviral activity against RNA respiratory viruses, including influenza A and B, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and respiratory syncytial virus (RSV). Sub-micromolar potency was observed for multiple compounds, with minimal cytotoxicity and inhibition of host DNA polymerases. Notably, the different modifications profoundly affected the antiviral spectrum, suggesting that despite lacking a hydrogen-bond donor, analogues with either 6-alkyl or 6-alkynyl substituents likely engage polymerases through distinct recognition mechanisms.
2026-09-24 | Solution structure, dynamics and fragment binding of unbound MERS-CoV nsp10
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) poses a significant public health threat, with a fatality rate of 37% and no approved therapeutics. Non-structural protein 10 (nsp10) is an essential cofactor that activates both the nsp14 3'-5' exoribonuclease (ExoN) activity required for RNA proofreading and the nsp16 2'-O-methyltransferase (2'-O-MTase) implicated in viral RNA cap formation. Despite its functional importance, the unbound structure and dynamics of MERS-CoV nsp10 in solution remain uncharacterised. Here we report a near-complete NMR backbone and sidechain assignment and characterise the solution structure and dynamics of the protein by NMR. In contrast to the folded α1 helix observed in crystal structures of coronavirus nsp10, we find that this region is intrinsically disordered in solution, with residues 10-22 undetectable under standard conditions and further evidenced by pH titration, temperature-dependent NMR, and CLEANEX-PM experiments. Analysis of NOE contacts confirmed that the core adopts the conserved coronavirus nsp10 fold, consistent with the AlphaFold-predicted structure. 15N backbone relaxation measurements indicated a rigid, well-ordered core with only localised flexibility, despite a relatively low proportion of secondary structure elements, and CPMG and CEST experiments detected no conformational exchange on the μs-ms timescale. Building on this structural and dynamic characterisation, we explored the ligandability of nsp10 by 19F NMR fragment screening. Screening of a 463-compound library identified 23 initial hits (4.97% hit rate), of which 20 were confirmed by 15N SOFAST-HMQC and eight gave quantifiable affinities by MST (Kd 0.5-6.9 mM), the remainder being too weak for reliable determination. Chemical shift perturbations clustered near functional surfaces of the folded core, indicating that MERS-CoV nsp10 is ligandable and providing chemical starting points for antiviral development.
2026-09-15 | Mutation-Aware Machine Learning Framework for Predicting Binding Affinity of Nirmatrelvir Analogs Targeting Coronavirus Main Proteases.
The emergence of resistance-associated mutations in coronavirus main protease (Mpro) poses a significant challenge to the development of broad-spectrum antiviral therapeutics. In this study, we improved and accelerated a mutation-aware machine learning (ML) framework to predict the binding score of Nirmatrelvir analogue ligands against wild-type and mutant MERS-CoV Mpro. A library of 15,889 Nirmatrelvir derivatives generated through systematic scaffold modification was docked against the wild-type and five variants of the Mpro, producing a total of 95,334 structural and docking score datasets of these protein-ligand complexes. During the ML model development phase, ligand effects were learned from RDKit molecular descriptors and graph-based representations, and the mutation-induced effects were captured through delta-encoded physicochemical properties (hydrophobicity, charge, aromaticity, and polarity) of the active-site residues. Among the evaluated models, the CatBoost regressor tree-based algorithm achieved the lowest mean absolute error (MAE) value of 0.23 Kcal/mol and an R2 of 0.87. Further improvement was achieved by creating a weighted ensemble model combining the CatBoost regressor, XGBoost and LightGBM regressor, resulting in a prediction accuracy with a MAE of 0.19 Kcal/mol and an R2 of 0.90 relative to docking scores. Model robustness was further evaluated through random-, ligand group- and scaffold group- K-fold cross-validation along with their Y-randomization. Moreover, the models were also tested with a new set of 1000 structurally diverse compounds. SHAP analysis was conducted, which identified 20 molecular descriptors critical for accurate predictions. The ensemble model accurately predicted the binding affinities of Nirmatrelvir and its four analogues (E1-E4), reproducing the experimental pIC50 trend and correctly identifying the most potent inhibitors. The ensemble model also showed consistent performance across all MERS-CoV Mpro variants, S147Y, S142G, L144A, S142G/S147Y, and S142G/L144A/S147Y, demonstrating its potential for rapidly discovering mutation-resistant antiviral drugs.
2026-09-02 | mTOR Signaling as a Central Regulator of Coronavirus Replication: Mechanistic Insights and Translational Opportunities
Coronaviruses comprise a diverse group of enveloped, positive-sense single-stranded RNA viruses capable of causing high morbidity in humans and livestock. The repeated emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 underscores the critical need for broad-spectrum countermeasures. Mounting evidence demonstrates that successful coronavirus infection depends on the manipulation of host cellular pathways governing translation, metabolism, autophagy, and survival. The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that functions via the mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2) to integrate extracellular and intracellular signals. Rather than remaining passive metabolic bystanders, coronaviruses actively exploit and rewrite host PI3K/Akt/mTOR networks to facilitate structural translation, assemble double-membrane replication organelles, suppress autophagic clearance, and reprogram protective innate and adaptive immune landscapes. This review provides a comprehensive synthesis of the molecular mechanisms dictating coronavirus–mTOR interactions across human pathogens and high-impact veterinary models. We detail the clinical consequences of dysregulated mTOR signaling—including immunometabolic perturbations, long-term metabolic memory, and tissue-specific complications—and evaluate the therapeutic potential of allosteric rapalogs, dual ATP-competitive inhibitors, and natural compounds as host-directed platforms designed to complement conventional antiviral regimens and enhance global pandemic preparedness.
2026-08-31 | Design, synthesis, and structural characterization of covalent tetrahydroquinoline-based inhibitors of coronavirus 3CLpro.
This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf, exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.
vaccines
2026-09-02 | An Engineered HR1-Stem Helix-HR2 Trimeric Platform for Developing Broad-Spectrum Coronavirus Vaccines.
The rapid spread of immune-evasive viral variants, exemplified by SARS-CoV-2, highlights the urgent need for broad-spectrum coronavirus vaccines. Although multimeric display of the receptor-binding domain (RBD) using exogenous scaffolds improve immune responses, such approaches may elicit off-target immune responses against the scaffolds themselves and remain limited by rapid RBD antigenic drift. Here, we report the rational design of a self-assembling trimeric subunit vaccine, termed RBD-heptad repeat 1 (HR1)-stem helix (SH)-heptad repeat 2 (HR2) (RHS), which integrates the JN.1 RBD with a highly conserved SH epitope from SARS-CoV-2 within a native HR1-HR2 trimeric scaffold via optimized linkers. RHS exhibits high structural stability, efficient trimerization, and enhanced antigen presentation. In mice, RHS elicits robust humoral and cellular immune responses, including potent cross- neutralizing antibodies against diverse SARS-CoV-2 variants and pan-betacoronavirus SH-specific antibodies. In K18-hACE2 mice, RHS confers strong protection against both antigen-matched and antigen-mismatched Omicron variants, while intranasal immunization induces potent mucosal IgA and IgG responses. Furthermore, the modular RHS platform is readily adaptable to antigens from SARS-CoV and MERS-CoV, underscoring its versatility for pan-coronavirus vaccine development. Together, these findings establish RHS as a generalizable strategy for overcoming viral immune evasion and advancing next-generation vaccine design.
2026-08-26 | Plant-Produced Vaccines for Protection from Human and Veterinary Coronaviruses.
Coronaviruses are responsible for numerous diseases causing substantial morbidity and mortality to both humans and animals. In particular, they have caused three significant outbreaks in humans including severe acute respiratory syndrome 1 (SARS-CoV-1), Middle East respiratory syndrome (MERS-CoV), and, most recently, the severe acute respiratory syndrome 2 (SARS-CoV-2) pandemic. Two relevant veterinary diseases are porcine transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV), which cause severe losses in the pork industry. While efficacious vaccines were developed in an unprecedented timeframe for COVID-19, vaccines have not been commercialized for other human coronaviruses and vaccines against animal coronaviruses have limited efficacy and logistical challenges in administration. There is a clear need for more efficacious vaccines with simpler methods of delivery and administration for both human and veterinary use. The production of subunit vaccines in plant systems holds great promise in addressing the current challenges and facilitate the preparation for future potential outbreaks and new viruses. This review will summarize the state of development of vaccines in plant systems including tobacco, rice, maize, and others.
2026-08-20 | Protective pan-betacoronavirus neutralizing antibodies by vaccination.
The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo . Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness. Epitope-focused S2 stem-helix nanoparticle immunogens elicit protective broadly neutralizing antibodies (bnAbs) against diverse betacoronaviruses in non-human primates, establishing a framework for development of pan-betacoronavirus vaccines.
2026-07-22 | Intranasal gold nanoparticle-antigen induces mucosal and systemic immunity against β-coronaviruses
The continued emergence of diverse beta-coronaviruses (β-CoVs) from animal reservoirs underscores the urgent need for broad-spectrum mucosal vaccines, yet their development is hindered by physiological barriers, rapid antigen clearance, and suboptimal multivalent display strategies. To address this, we intranasally immunized BALB/c mice ( n = 3 or 4 per group) with 5 or 15 nm gold nanoparticles (AuNPs) displaying the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD, 5 μg per mouse) and adjuvanted with the STING agonist cGAMP (20 μg per mouse). Guided by the serotyping of STING agonist-elicited neutralizing responses, we generated AuNP-Mix co-displaying six representative β-CoV RBDs for comparative immunological evaluation against single-RBD AuNP formulations. Antigen delivery, pulmonary retention, mucosal and systemic immune responses were evaluated via in vivo imaging, enzyme-linked immunosorbent assays, pseudovirus neutralization assays, flow cytometry, immunofluorescence, and challenge studies. We demonstrated that 5 nm AuNP-RBD adjuvanted with cGAMP exhibited superior mucosal penetration and lung retention, induced robust local and systemic immunity, and elicited cross-neutralizing antibodies against SARS-CoV-2 variants, SARS-CoV, and SARS-related coronaviruses. Intranasal immunization with AuNP-Mix elicited broader mucosal/systemic immune responses than those achieved with simple RBD mixtures, as demonstrated by its potent neutralizing activity against SARS-CoV-2 variants, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and divergent MERS-like viruses. These findings establish AuNP-based mosaic display as a versatile platform for next-generation mucosal vaccines.
2026-07-01 | Minor differences in the untranslated regions of measles vector additional transcription units are reflected by differential immunogenicity of encoded MERS-CoV Spike antigen.
The recombinant measles virus (MeV) is among those vaccine platform technologies, which are tested for the fast generation of effective vaccines against other pathogens, such as emerging virus diseases. Different live-attenuated vaccine strains have become available as backbones, with few differences. Here, we analyze how minor differences of recombinant Moraten (MVvac2) or Schwarz (MVSchw) constructs have an impact on the performance of respective derived Middle East respiratory syndrome (MERS) vaccine candidates. MVvac2 or MVSchw viruses, both encoding the Spike glycoprotein (S) of the MERS-coronavirus (MERS-CoV) in an additional transcription unit (ATU) between the hemagglutinin gene and the polymerase gene L cassette, were tested. Both robustly expressed the additional gene. However, approximately twofold to threefold higher amounts of S proteins were observed in cells infected by the MVSchw-MERS-S(H) virus, correlating with the same relative ratio of S mRNA found in these cells. Exchange of the short genomic 3' UTR ATU sequence in MVvac2 against the sequence in MVSchw enhanced gene expression by about the same factor and demonstrates causality. MeV-susceptible IFNAR-/--CD46Ge mice vaccinated with either candidate reveal that higher relative S antigen expression by MVSchw-MERS-S(H) tended toward induction of higher specific antibody titers, but lower numbers of S antigen-specific T cells. In subsequent challenge experiments, both candidates were effective. Thus, minor differences in the genetic composition of recombinant MeV's ATU may modulate the gene expression pattern of additionally encoded proteins that are reflected by changes in the respective immunogenicities, but which were not decisive for protection in the chosen disease model. In case of emerging or re-emerging infections, vaccine platform technologies are needed to rapidly develop effective vaccines to aid public healthcare in pandemics. Besides mRNA vaccines, also viral platform technologies, that is, the adenovirus-derived vaccines Vaxzevria and JCOVDEN, have proven to be of immense value during the COVID-19 pandemic. For future pandemics, it is crucial to understand the factors in vector design that modulate immunogenicity. This knowledge allows the tailoring of vaccine vectors to fit specific target product profiles, for example, to build vectors which trigger an accentuated T cell or, alternatively, antibody response against an antigen of interest. Our study using the live-attenuated measles vaccine backbone as a promising example is therefore crucial in demonstrating that very minor differences in the vaccine backbone can alter the antigen expression profile of the vector-antigen system and impact the relative induction of T-cell or antibody responses against the added target antigen.
other
2026-08-13 | Genotype to phenotype consequences in MERS-CoV
Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia in 2012 and has a reported mortality rate of 36%, making it the most pathogenic human coronavirus known. Dromedary camels are the major reservoir of MERS-CoV, with regular spillover into humans presenting a significant public health risk. Human-to-human transmission has been confirmed between close contacts in healthcare settings and those residing in the same household. Currently, there are no specific medical countermeasures available to treat MERS-CoV infection. Much of the MERS-CoV research to date has focussed on the EMC/2012 reference strain, which is phylogenetically classified as clade A. However, clade A viruses have been considered extinct since 2015, while the majority of MERS-CoV strains causing human infections belong to clade B, lineage 5. It was hypothesised that naturally occurring Spike mutations identified in human MERS-CoV infections would result in phenotypic differences in virus entry and neutralisation. It was also hypothesised that contemporary MERS-CoV strains would replicate and adapt differently in humans relative to EMC/2012. Therefore, it is important to understand the genotype to phenotype consequences in contemporary MERS-CoV strains to increase knowledge surrounding human infections. This will also facilitate a more effective response to virus adaptation and improve pandemic preparedness. Here, two tools were developed to study contemporary MERS-CoV: a lentiviral pseudotyping system and a yeast-based reverse genetics system. Pseudotypes were used to characterise naturally occurring Spike mutations identified in human MERS-CoV sequences. Split GFP cell-cell fusion assays demonstrated that I529T, E536K, L745F and Ins885 improved MERS-CoV entry. While microneutralisation assays demonstrated that L411F, T424I, L506F, L745F and T746K increased resistance to neutralisation by pooled patient sera. A recombinant MERS-CoV (rMERS-CoV) full-length infectious clone carrying a representative clade B, lineage 5 sequence was generated via reverse genetics. rMERS-CoV was subsequently used to study infectivity, replication and genetic stability of contemporary strains in human cells. Replication of rMERS-CoV in primary human nasal epithelial cells was found to be improved relative to EMC/2012. Additionally, the host response to rMERS-CoV infection was investigated in Calu-3 cells, whereby significantly upregulated genes included those associated with the innate immune response and cellular stress response elements. Ultimately, the evidence presented here indicates contemporary MERS-CoV strains may be becoming more infectious in humans, while also carrying mutations that facilitate immune evasion. Crucially, contemporary MERS-CoV replicated to significantly higher titres than EMC/2012 in an in vitro model of the upper respiratory tract. These findings highlight the importance of continued surveillance and study of contemporary strains to manage the pandemic threat posed by MERS-CoV. Furthermore, in addition to being used alongside surveillance systems, the tools developed in this thesis could be used in the development of therapeutics to treat MERS disease.
2026-04-22 | Comparative genomics identifies small interfering RNA with activity against all five human betacoronaviruses.
BACKGROUND: The Orthocoronavirinae virus subfamily (CoV) poses a continuous global health threat. Seven CoV species are known to infect humans and additional animal CoVs with potential for human spillover have been identified. Currently, antiviral drugs are available only against SARS-CoV-2, underscoring the need for broad-spectrum antivirals. Targeting the viral RNA genome with small interfering RNAs (siRNAs) induces its degradation by endogenous nucleases and represents an effective strategy to inhibit CoV replication. Previous studies have demonstrated the efficacy and feasibility of this approach against individual CoV species. However, its potential to serve as a broad-spectrum antiviral strategy effective across multiple members of the CoV subfamily has not been systematically explored. METHODS: The conservation of all potential siRNA target sites within the CoV genome (n ≈ 30,000) was analyzed using a custom database comprising 250,000 full-length genome sequences from 44 CoV species isolated from diverse mammalian and avian hosts. Antiviral activity of selected siRNA candidates was screened using a replication-competent recombinant SARS-CoV-2 expressing green fluorescent protein. The effect of target site mismatches was assessed using luciferase reporters, and cross-species antiviral activity was evaluated against six representative wild-type CoVs. Cellular toxicity was investigated by monitoring cell death, confluence, metabolic activity, and in silico prediction of siRNA off-target activity. RESULTS: Conservation of potential siRNA target sites correlated with the evolutionary distance between CoV species. Several genomic regions were conserved across different CoV subgenera and genera, but no site was universally preserved across all 44 analyzed species. The antiviral activity and tolerability of 347 siRNAs targeting the most promising sites were evaluated in multiple screening rounds. Following optimization of siRNA design and chemistry, we identified a lead candidate, si117m, which displayed high tolerability and potent silencing activity at picomolar concentrations against target sites of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43 and HCoV-HKU1. CONCLUSIONS: Our study demonstrates the potential of comparative genomics for developing broad-spectrum antiviral siRNAs. We identified a lead siRNA, si117m, which combines a favorable safety profile with cross-species activity against five human CoVs, supporting its potential for clinical translation and future pandemic preparedness.
2026-04-10 | QStrain: an interactive platform for viral genome analysis and nucleic acid therapeutic design
Abstract Background QStrain is an integrated resource platform designed to facilitate viral genome analysis and the rational design of nucleic acid therapeutics. Results The system integrates reference-guided multiple sequence alignment of high-risk viral pathogens, including Severe Acute Respiratory Syndrome Coronavirus 2, Lassa virus, Severe Fever with Thrombocytopenia Syndrome virus, Middle East Respiratory Syndrome Coronavirus, Influenza A virus subtype H5N1 and H7N9, Nipah virus, Respiratory Syncytial Virus, and Dengue virus, with a growing database of viral genomes. QStrain provides versatile visualization modules such as frequency profiles, conservation scores, RNA expression patterns, and phylogenetic trees to enhance the interpretation of viral sequence variation. By identifying highly conserved genomic regions, QStrain supports the prediction of candidate therapeutic targets and enables the automated design of small interfering RNA (siRNA) and antisense oligonucleotides (ASOs). Additional features include off-target searching and 2D structure viewing for comprehensive assessment of therapeutic potential. Conclusions Ultimately, QStrain ( https://qstrain.sookmyung.ac.kr ) provides a critical, user-friendly framework to accelerate the design pipeline of nucleic acid-based therapies, enhancing preparedness against current and future viral outbreaks.
2026-02-28 | Unveiling the epitope repertoires and protective roles of MERS-CoV-specific T cells in mice.
Since its initial emergence in 2012, MERS-CoV has remained endemic and a global health threat. While accessory proteins (ORFs) are known for immune evasion, their role in adaptive immunity is unexplored. This study systematically investigated T cell responses against MERS-CoV ORFs. We mapped epitope repertoires targeting structural proteins and ORFs in C57BL/6 and BALB/c mice, revealing that ORFs potently induced virus-specific T cells. Notably, ORF5 induced the dominant CD8+ T cell responses in BALB/c mice. Further analysis revealed that ORF4b208-specific CD4+ and ORF5167-specific CD8+ T cells in the respiratory tract exhibited polyfunctional cytokine profiles, high antigen sensitivity, and potent in vivo cytotoxicity. These specific T cells played protective roles during MERS-CoV infection by promoting viral clearance. Collectively, this study identified MERS-CoV-specific T cell epitopes and elucidated the roles of ORF4b- and ORF5-specific T cells, enhancing our understanding of anti-MERS-CoV T cell responses and advancing vaccine design strategies against MERS-CoV.
2025-12-10 | MERS-CoV RBD-mRNA Presents Better Immunogenicity and Protection than the Spike-mRNA.
Pathogenic Middle East respiratory syndrome CoV (MERS-CoV), first identified in Saudi Arabia in 2012, continues to pose a threat to public health. The trimeric spike (S) protein of MERS-CoV binds to the cellular receptor through the receptor-binding domain (RBD) in the S1 subunit to initiate virus entry and infection. Therefore, both the S protein and its RBD are targets for the development of MERS-CoV vaccines. Nevertheless, a direct comparison of the immune efficiency of S- and RBD-based MERS-CoV vaccines has not been made. Here, we compared two mRNA vaccines, respectively, targeting the S (S-mRNA) and RBD (RBD-mRNA) of MERS-CoV for their durable immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Both mRNAs encapsulated with lipid nanoparticles (LNPs) maintained strong stability at various temperatures during the detection period. LNP-encapsulated RBD-mRNA elicited significantly higher and more durable antibodies than LNP-encapsulated S-mRNA, maintaining stronger and broadly neutralizing activity against the MERS-CoV original strain, as well as multiple variants containing key mutations within the RBD region. Importantly, RBD-mRNA provided durable protective efficacy against MERS-CoV infection in middle-aged mice, and this protection was associated positively with serum neutralizing antibody titers. Overall, this study identifies RBD-mRNA as an effective vaccine against MERS-CoV, with great potential for further development.
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Drug Discovery Landscape
2 orphan drug designations for Middle East respiratory syndrome, including 1 approved therapy.
2 orphan drug designations for Middle East respiratory syndrome, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Interferon alfa-n3 | proteins | EMA | — | NV Hemispherx BioPharma Europe |
Respiratory syncytial virus immune globulin (Human) [Respigam] | — | FDA | Approved | MedImmune & Massachussetts Public Health Biologics Labs. |
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