Twin engines of viral replication: Medicinal chemistry insights on SARS-CoV-2 nsp12 and nsp13

The SARS-CoV-2 pandemic highlighted the urgent need for antivirals targeting essential viral enzymes. Herein, we critically examine the current landscape of small molecule inhibitors targeting the highly conserved non-structural protein 12 (nsp12), the RNA-dependent RNA polymerase, and non-structural protein 13 (nsp13), the helicase, both critical for viral genome replication. Structural and mechanistic features that inform rational inhibitor design, including active sites and cofactor interactions, are discussed. For nsp12, nucleoside analogues derived from a drug repurposing strategy, as well as emerging non-nucleoside inhibitors targeting allosteric sites, are evaluated. Development of ATPase and helicase inhibitors for nsp13 is at an earlier stage, but promising scaffolds have been revealed through high-throughput and structure-based screening. An in-depth analysis of small molecule inhibitors from synthetic and natural sources is presented for both enzymes, highlighting key limitations and strategic directions to advance the development of next-generation antivirals against SARS-CoV-2 through targeted modulation of nsp12 and nsp13.