RNA synthesis and substrate analog inhibition in the CCHFV polymerase

A team of researchers led by scientists from the Wuhan Institute of Virology, Chinese Academy of Sciences, has published findings on the structure and function of the Crimean-Congo hemorrhagic fever virus (CCHFV) polymerase, offering new insights into potential antiviral strategies. The study, published in Nature on 22 July 2026, presents detailed structural analyses of the large L protein from CCHFV, which belongs to the Nairoviridae family. This protein, consisting of approximately 4000 amino acid residues, is among the largest known viral polymerases and lacks comprehensive structural information until now. The research team, including Hengxia Jia, Bo Tang, Shunli Liu, Xin Wen, Fan Wu, Xiao Hu, Hu Zhou, Tingting Chong, Lincan Lv, Qiaojie Liu, Guibo Rao, Mingyu Wei, Xuping Jing, Sheng Cao, Fei Deng, Zhihong Hu, Bo Shu, Rui Gong, Jiqin Wu, Manli Wang, and Peng Gong, used advanced techniques to determine the structure of the full-length CCHFV L protein and its associated polymerase elongation complex. The structure was resolved at a resolution of 3.0 Å, revealing key features of the enzyme's function during both early and late stages of RNA synthesis. The findings suggest that the CCHFV polymerase contains large insertions and modifications within its three main functional domains, endonuclease, RNA-dependent RNA polymerase (RdRP), and cap-binding domain, which contribute to its unique enzymatic properties. One of the key discoveries involves the role of nucleotide analogs (NAs) in inhibiting the activity of the CCHFV RdRP. The study identified specific NAs with ribose-2′-modifications similar to those found in the hepatitis C drug sofosbuvir. These compounds were shown to effectively block the polymerase activity by causing immediate chain termination, thereby preventing the virus from replicating its genome. The effectiveness of these NAs was further validated using competition assays against corresponding NTPs, drawing parallels with the sofosbuvir-hepatitis C virus RdRP system. The research also highlights the importance of RNA binding pathways and interaction networks formed around the RdRP active site. These elements appear crucial for efficient viral replication, as supported by data from CCHFV minigenome assays. The structural and biochemical insights gained from this study could pave the way for the development of novel antiviral agents targeting the CCHFV polymerase. The work was conducted primarily at the State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, with additional contributions from the Drug Discovery Center for Infectious Diseases at Nankai University. The collaboration involved multiple institutions, reflecting the interdisciplinary nature of modern virological research. Further studies are needed to explore the therapeutic potential of these NAs in vivo and to assess their efficacy against different strains of CCHFV. Researchers are currently working on optimizing the chemical structures of these analogs to enhance their stability and reduce potential side effects. The ultimate goal is to translate these laboratory findings into effective treatments for patients infected with CCHFV.