Interface‐based design of the favipiravir‐binding site in SARS‐CoV‐2 RNA‐dependent RNA polymerase reveals mutations conferring resistance to chain termination

Padhi, Aditya K.; Dandapat, Jagneshwar; Saudagar, Prakash; Uversky, Vladimir N.; Tripathi, Timir

Favipiravir is a broad‐spectrum inhibitor of viral RNA‐dependent RNA polymerase (RdRp) currently being used to manage COVID‐19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain‐termination mechanism utilized by favipiravir, we used high‐throughput interface‐based protein design to generate > 100 000 designs of the favipiravir‐binding site of RdRp and identify mutational hotspots. We identified several single‐point mutants and designs having a sequence identity of 97%–98% with wild‐type RdRp, suggesting that SARS‐CoV‐2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV‐GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS‐CoV‐2 against favipiravir.