GoKawiilThe about 4000-residue L proteins from the Nairoviridae are the largest known viral polymerases, lacking global structural information and promising nucleotide analog (NA) inhibitors. Here we report structures of full-length Nairoviridae Crimean-Congo hemorrhagic fever virus (CCHFV) L including a 3.0-Å-resolution polymerase elongation complex that elucidates mechanisms of both early and late elongation stages. Large additions and insertions are found in all three major functional regions that contain the endonuclease, RNA-dependent RNA polymerase (RdRP), and cap-binding domain of CCHFV L, extending RNA binding paths on both sides of RdRP active site and creating interaction networks critical for virus replication as suggested by CCHFV minigenome assay data. NAs with ribose-2′-modifications identical to the hepatitis C drug sofosbuvir are found to specifically and efficiently inhibit CCHFV RdRP through immediate chain termination mechanism. Using sofosbuvir-hepatitis C virus RdRP system as the reference, the potency of these NAs is further demonstrated in competition assays in the presence of corresponding NTPs.
RNA synthesis and substrate analog inhibition in the CCHFV polymerase
Why This Matters
This research provides critical insights into the structure and function of the large CCHFV polymerase, revealing new mechanisms of viral RNA synthesis and identifying effective nucleotide analog inhibitors like sofosbuvir. These findings could accelerate the development of targeted antiviral therapies against CCHFV, a significant threat to global health, and inform broader antiviral drug design strategies. Understanding these mechanisms is vital for advancing antiviral research and improving preparedness against viral outbreaks.
Key Takeaways
- Detailed structures of CCHFV polymerase reveal new RNA binding pathways.
- Nucleotide analogs like sofosbuvir effectively inhibit CCHFV replication.
- Findings support targeted antiviral drug development for Nairoviridae viruses.
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