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| Title | Structures and inhibition of the Crimean-Congo haemorrhagic fever virus polymerase. |
|---|---|
| Journal, issue, pages | Nature, Year 2026 |
| Publish date | Jul 22, 2026 |
Authors | Lu Xue / Jiacheng Gui / Hainei Pan / Fan Wu / Shenghua Gao / Wenhua Kuang / Tiancai Chang / Zimu Li / Binqian Zou / Heyu Zhao / Mei Li / Min Zhou / Hongyu Yuan / Lijun Rong / Peng Gong / Jun He / Zengqin Deng / Manli Wang / Peng Zhan / Xinwen Chen / Xiaoli Xiong / ![]() |
| PubMed Abstract | 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 ...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 countermeasures. 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. ) and the nucleoside analogue 2'-deoxy-2'-fluorocytidine, 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. |
External links | Nature / PubMed:42486991 |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 1.85 - 3.09 Å |
| Structure data | EMDB-66754, PDB-9xd4: EMDB-66755, PDB-9xd5: EMDB-66756, PDB-9xd6: EMDB-66783, PDB-9xe6: EMDB-66784, PDB-9xe7: EMDB-66785, PDB-9xe9: EMDB-66787, PDB-9xec: ![]() PDB-9xf9: |
| Chemicals | ![]() ChemComp-ZN: ![]() ChemComp-2KH: ![]() ChemComp-MN: ![]() PDB-1ezw: ![]() ChemComp-HOH: |
| Source |
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Keywords | VIRAL PROTEIN / RNA polymerase / VIRUS / VIRAL PROTEIN/RNA / VIRAL PROTEIN-RNA complex / HYDROLASE / cap-snatching endonuclease / inhibitor |
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crimean-congo hemorrhagic fever virus strain ibar10200
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