Viral polymerases of the Nairoviridae family are unusually large, and until now their atomic details have remained largely unexplored. In a new study, researchers report near-complete structural views of the full-length polymerase (L) from Crimean-Congo hemorrhagic fever virus (CCHFV), the causative agent of a severe tick-borne hemorrhagic illness. With global architecture previously missing, the work also opens a clear path for rational antiviral design targeting the RNA synthesis machinery.
Using high-resolution cryo-EM, the team solved structures covering the polymerase elongation cycle. A key accomplishment is a polymerase elongation complex at 3.0 Å resolution, capturing CCHFV L engaged with RNA and substrate in an informative intermediate state. This provides mechanistic insight into how the enzyme performs both early and later stages of RNA elongation.
The structures reveal that CCHFV L contains pronounced additions and insertions across three major functional regions: an endonuclease module, an RNA-dependent RNA polymerase (RdRP) center, and a cap-binding domain. Rather than behaving like a simple scaffold, these expanded segments remodel the geometry of RNA engagement.
Notably, the additional elements extend RNA binding paths on both sides of the RdRP active site. This reshaping likely helps stabilize the nascent RNA and coordinate product movement through the polymerase channel. Together, the interfaces form interaction networks that are consistent with experimental evidence from CCHFV minigenome assays.
To translate structure into therapy, the study evaluates nucleotide analog inhibitors (NAs) carrying ribose 2′-modifications identical to those found in the hepatitis C drug sofosbuvir. The analogs specifically and efficiently inhibit CCHFV RdRP, acting through an immediate chain termination mechanism during RNA synthesis.
Structural and biochemical observations align with the idea that the analogs are incorporated into the growing RNA chain, after which elongation halts rapidly. This “stop” effect contrasts with delayed termination pathways sometimes observed for other substrate mimics.
To further validate mechanism and potency, the researchers employ sofosbuvir–hepatitis C virus RdRP as a reference and perform competition assays in the presence of corresponding natural nucleotides (NTPs). These experiments demonstrate how competing substrates influence inhibitor performance, supporting the NA-specific engagement of the CCHFV RdRP active site.
Overall, the work delivers both a detailed blueprint of CCHFV L RNA synthesis and a compelling antiviral strategy. By pinpointing structural determinants and showing rapid chain termination by clinically known analog chemistry, the study advances Viral Science News coverage toward actionable inhibitor development against this high-consequence pathogen.
Subject of Research: CCHFV polymerase structure and nucleotide analog inhibition
Article Title: RNA synthesis and substrate analog inhibition in the CCHFV polymerase
Article References: Jia, H., Tang, B., Liu, S. et al. RNA synthesis and substrate analog inhibition in the CCHFV polymerase. Nature (2026). https://doi.org/10.1038/s41586-026-10913-w
Image Credits: AI Generated
DOI: 10.1038/s41586-026-10913-w
Keywords: Crimean-Congo hemorrhagic fever virus, Nairoviridae, L polymerase, RdRP, elongation complex, cryo-EM, nucleotide analog, sofosbuvir, chain termination, minigenome assay
