RARE DISEASE
Crimean-Congo hemorrhagic fever
Crimean-Congo hemorrhagic fever
Crimean-Congo hemorrhagic fever
Synonyms: CCHF, Congo fever, Congo hemorrhagic fever, Crimean hemorrhagic fever
Synonyms: CCHF, Congo fever, Congo hemorrhagic fever, Crimean hemorrhagic fever
Synonyms: CCHF, Congo fever, Congo hemorrhagic fever, Crimean hemorrhagic fever
Drug discovery
1
drug
With orphan designation
Overview
Crimean-Congo hemorrhagic fever (CCHF) is a tickborne Nairovirus infection causing severe viral hemorrhagic fever. Transmission occurs via Hyalomma ticks, contact with infected animal tissues, or human bodily fluids. Symptoms include sudden fever, myalgia, petechial rash, hemorrhage (days 3–5), and multiorgan failure, with a case fatality rate of 10%–40% [1][7][17]. Diagnosis relies on PCR or serology. Prevention focuses on tick avoidance, PPE in high-risk settings, and ribavirin prophylaxis for exposures [3][11][18].
Burden
Annual global incidence: ~10,000–15,000 cases, with underreporting in low-resource regions [1][4]
CFR ranges from 5% in well-resourced settings to 40% in Africa; indirect costs from livestock trade disruptions [5][9][15]
Emerging threat due to climate-related tick expansion and inadequate surveillance infrastructure [10][12]
Therapies
Supportive care: Fluid resuscitation, blood product transfusions, and organ support [3][11][18]
Ribavirin: Used off-label despite conflicting efficacy data; WHO recommends its use in high-risk exposures [3][7][19]
Infection control: Strict isolation and biocontainment protocols to prevent nosocomial transmission [16][18]
Categories: rare infectious diseases
Research Papers
501 drug discovery papers about Crimean-Congo hemorrhagic fever, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
501 drug discovery papers about Crimean-Congo hemorrhagic fever, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-05 | Pathogenicity and virulence of Crimean-Congo hemorrhagic fever virus: From enzootic maintenance to severe human disease
Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), an enveloped, negative-sense, tri-segmented RNA virus in the genus Orthonairovirus. The virus is endemic across Africa, the Middle East, Asia, and Europe, shaped by the ecology of ixodid ticks and their wildlife hosts. While infection in most vertebrates is asymptomatic, human disease ranges from mild illness to fulminant hemorrhagic fever with vascular leak, multiorgan failure, coagulopathy, and shock, with case-fatality rates up to 30% and no licensed countermeasures. This review synthesizes current understanding of CCHFV pathogenicity and virulence across its enzootic cycle. We highlight host and viral factors driving infection in ticks, intermediate hosts, and humans, including entry, immune evasion, and mechanisms underlying severe disease. We also identify key knowledge gaps and research priorities to advance understanding of CCHFV pathogenesis and inform strategies to mitigate severe disease.
2026-07-28 | Repurposing Small-molecule Inhibitors against Bunyaviruses: Advances, Mechanisms, and Therapeutic Prospects.
Bunyaviricetes, including highly pathogenic members such as Severe Fever with Thrombocytopenia Syndrome Virus, Crimean-Congo Hemorrhagic Fever Virus, and Rift Valley Fever Virus, pose significant global health threats characterized by high mortality rates and a lack of approved specific therapeutics. Drug repurposing provides pharmaceutical companies with cost-effective and expedited strategies to discover innovative treatment options for patients. Given the issue of antiviral drug resistance and the high cost of developing new antiviral drugs, drug repurposing offers enormous potential for expanding the repertoire of available therapeutics. This paper reviews the progress made in developing candidate drugs against bunyaviruses through high-throughput screening and drug repurposing methods, summarizes the mechanisms of action of candidate drugs targeting viruses and host cells, and looks ahead to future trends in the development of small-molecule antiviral drugs, with the aim of providing a reference for promoting the development of new bunyavirus drugs.
2026-07-23 | Structures and inhibition of the Crimean-Congo haemorrhagic fever virus polymerase.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus and causes severe, often fatal, human infections. Lacking licensed vaccines or drugs, CCHFV is a World Health Organization priority pathogen requiring urgent development of medical countermeasures1,2. The CCHFV Large (L) protein functions as the viral RNA-dependent RNA polymerase CCHFV-L, representing a promising antiviral target, and is among the largest viral polymerases in the order Bunyavirales. Here we define the cofactors required for CCHFV-L RNA synthesis in vitro, enabling capture and determination of elongating CCHFV-L-RNA complex structures. The structures show a markedly enlarged polymerase architecture, revealing that CCHFV-L RNA synthesis is accompanied by ordering of the polymerase peripheral domains. We also define how the baloxavir-derived experimental drug WXSH0208 (ref. 3) and the nucleoside analogue 2'-deoxy-2'-fluorocytidine4,5, which has nanomolar cellular potency, inhibit this polymerase through endonuclease inhibition and post-translocation chain termination, respectively. Together, these results should structurally guide rational optimization of inhibitors directed against CCHFV-L.
2026-07-21 | The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV)
The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV) Mohammad M. Sajadi and Scott D. Pegan discuss leveraging cross-reactive monoclonals and next-generation vaccines to address Crimean-Congo hemorrhagic fever virus diversity. Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic negative (-) sense RNA bunyavirus of the Nairoviridae family. CCHFV is widely distributed across Africa and wide swaths of Europe and Asia. It has also recently emerged, with fatal consequences, in the previously CCHFV-naïve country of Spain and has been detected in ticks in France. This underscores the virus’s propensity to continue spreading wherever its Hyalomma tick vector can gain a foothold. (1) Typical mortality rates for CCHFV range from 2-40% in hospitalized cases. (2) As additional countries are becoming at risk and the potential for significant human-to- human transmission increases, CCHFV is considered a dangerous human pathogen by the international community. It is also an NIAID prototype virus for several Nairovirus pathogens that can cause human disease of varying severity.(3)
2026-07-15 | Structure-Guided Discovery and Biochemical Validation of Novel Small-Molecule Inhibitors Predicted to Target the CCHFV OTU Protease Y89-W99 Pocket.
Crimean-Congo hemorrhagic fever virus (CCHFV) remains a major public health threat due to its high mortality rates and the absence of approved antiviral therapies. The viral ovarian tumor (OTU) protease is a critical virulence factor that suppresses host innate immunity through its deubiquitinase activity, making it an attractive therapeutic target. In this study, we employed a structure-guided approach to identify and validate novel small-molecule inhibitors targeting the non-catalytic Y89-W99 pocket of the OTU protease. Recombinant OTU protease was successfully expressed, purified, and refolded, yielding a soluble and enzymatically active protein. Cellular assays confirmed that the enzyme retains robust deubiquitinase activity, significantly reducing global ubiquitin conjugates in mammalian cells. In silico analysis of a putative DUB inhibitor library identified several candidate inhibitors with favorable binding interactions within the Y89-W99 pocket. Biochemical validation using a fluorometric Ub-AMC assay revealed that multiple small molecules strongly inhibit OTU activity, including OTUi-10 (~93% inhibition), OTUi-13 (~87%), OTUi-1 (~85%), OTUi-4 and OTUi-11 (~81%), and OTUi-9 (~76%). Additional moderate inhibitors included OTUi-12 (~67%), OTUi-19 and OTUi-21 (~66%), and OTUi-5 (~57%). In silico drug-likeness and toxicity profiling filtered the library to four fully compliant candidates, OTUi-4, OTUi-10, OTUi-11, and OTUi-12, all free of predicted toxicity alerts. These findings suggest that the Y89-W99 pocket may be a pharmacologically relevant site worthy of further investigation and identify OTUi-10, OTUi-4, and OTUi-11 as promising preliminary hit compounds. The results also provide initial insights that may guide future optimization and mechanistic studies of OTU protease inhibitors targeting CCHFV.
2026-08-05 | Pathogenicity and virulence of Crimean-Congo hemorrhagic fever virus: From enzootic maintenance to severe human disease
Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), an enveloped, negative-sense, tri-segmented RNA virus in the genus Orthonairovirus. The virus is endemic across Africa, the Middle East, Asia, and Europe, shaped by the ecology of ixodid ticks and their wildlife hosts. While infection in most vertebrates is asymptomatic, human disease ranges from mild illness to fulminant hemorrhagic fever with vascular leak, multiorgan failure, coagulopathy, and shock, with case-fatality rates up to 30% and no licensed countermeasures. This review synthesizes current understanding of CCHFV pathogenicity and virulence across its enzootic cycle. We highlight host and viral factors driving infection in ticks, intermediate hosts, and humans, including entry, immune evasion, and mechanisms underlying severe disease. We also identify key knowledge gaps and research priorities to advance understanding of CCHFV pathogenesis and inform strategies to mitigate severe disease.
2026-07-28 | Repurposing Small-molecule Inhibitors against Bunyaviruses: Advances, Mechanisms, and Therapeutic Prospects.
Bunyaviricetes, including highly pathogenic members such as Severe Fever with Thrombocytopenia Syndrome Virus, Crimean-Congo Hemorrhagic Fever Virus, and Rift Valley Fever Virus, pose significant global health threats characterized by high mortality rates and a lack of approved specific therapeutics. Drug repurposing provides pharmaceutical companies with cost-effective and expedited strategies to discover innovative treatment options for patients. Given the issue of antiviral drug resistance and the high cost of developing new antiviral drugs, drug repurposing offers enormous potential for expanding the repertoire of available therapeutics. This paper reviews the progress made in developing candidate drugs against bunyaviruses through high-throughput screening and drug repurposing methods, summarizes the mechanisms of action of candidate drugs targeting viruses and host cells, and looks ahead to future trends in the development of small-molecule antiviral drugs, with the aim of providing a reference for promoting the development of new bunyavirus drugs.
2026-07-23 | Structures and inhibition of the Crimean-Congo haemorrhagic fever virus polymerase.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus and causes severe, often fatal, human infections. Lacking licensed vaccines or drugs, CCHFV is a World Health Organization priority pathogen requiring urgent development of medical countermeasures1,2. The CCHFV Large (L) protein functions as the viral RNA-dependent RNA polymerase CCHFV-L, representing a promising antiviral target, and is among the largest viral polymerases in the order Bunyavirales. Here we define the cofactors required for CCHFV-L RNA synthesis in vitro, enabling capture and determination of elongating CCHFV-L-RNA complex structures. The structures show a markedly enlarged polymerase architecture, revealing that CCHFV-L RNA synthesis is accompanied by ordering of the polymerase peripheral domains. We also define how the baloxavir-derived experimental drug WXSH0208 (ref. 3) and the nucleoside analogue 2'-deoxy-2'-fluorocytidine4,5, which has nanomolar cellular potency, inhibit this polymerase through endonuclease inhibition and post-translocation chain termination, respectively. Together, these results should structurally guide rational optimization of inhibitors directed against CCHFV-L.
2026-07-21 | The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV)
The growing public health concern of Crimean-Congo Hemorrhagic Fever Virus (CCHFV) Mohammad M. Sajadi and Scott D. Pegan discuss leveraging cross-reactive monoclonals and next-generation vaccines to address Crimean-Congo hemorrhagic fever virus diversity. Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic negative (-) sense RNA bunyavirus of the Nairoviridae family. CCHFV is widely distributed across Africa and wide swaths of Europe and Asia. It has also recently emerged, with fatal consequences, in the previously CCHFV-naïve country of Spain and has been detected in ticks in France. This underscores the virus’s propensity to continue spreading wherever its Hyalomma tick vector can gain a foothold. (1) Typical mortality rates for CCHFV range from 2-40% in hospitalized cases. (2) As additional countries are becoming at risk and the potential for significant human-to- human transmission increases, CCHFV is considered a dangerous human pathogen by the international community. It is also an NIAID prototype virus for several Nairovirus pathogens that can cause human disease of varying severity.(3)
2026-07-15 | Structure-Guided Discovery and Biochemical Validation of Novel Small-Molecule Inhibitors Predicted to Target the CCHFV OTU Protease Y89-W99 Pocket.
Crimean-Congo hemorrhagic fever virus (CCHFV) remains a major public health threat due to its high mortality rates and the absence of approved antiviral therapies. The viral ovarian tumor (OTU) protease is a critical virulence factor that suppresses host innate immunity through its deubiquitinase activity, making it an attractive therapeutic target. In this study, we employed a structure-guided approach to identify and validate novel small-molecule inhibitors targeting the non-catalytic Y89-W99 pocket of the OTU protease. Recombinant OTU protease was successfully expressed, purified, and refolded, yielding a soluble and enzymatically active protein. Cellular assays confirmed that the enzyme retains robust deubiquitinase activity, significantly reducing global ubiquitin conjugates in mammalian cells. In silico analysis of a putative DUB inhibitor library identified several candidate inhibitors with favorable binding interactions within the Y89-W99 pocket. Biochemical validation using a fluorometric Ub-AMC assay revealed that multiple small molecules strongly inhibit OTU activity, including OTUi-10 (~93% inhibition), OTUi-13 (~87%), OTUi-1 (~85%), OTUi-4 and OTUi-11 (~81%), and OTUi-9 (~76%). Additional moderate inhibitors included OTUi-12 (~67%), OTUi-19 and OTUi-21 (~66%), and OTUi-5 (~57%). In silico drug-likeness and toxicity profiling filtered the library to four fully compliant candidates, OTUi-4, OTUi-10, OTUi-11, and OTUi-12, all free of predicted toxicity alerts. These findings suggest that the Y89-W99 pocket may be a pharmacologically relevant site worthy of further investigation and identify OTUi-10, OTUi-4, and OTUi-11 as promising preliminary hit compounds. The results also provide initial insights that may guide future optimization and mechanistic studies of OTU protease inhibitors targeting CCHFV.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Crimean-Congo hemorrhagic fever.
1 orphan drug designation for Crimean-Congo hemorrhagic fever.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ribavirin | small molecules | EMA | 2018-03-21 | — | Pharmadev Healthcare Ltd |
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