<i>S</i>-adenosylhomocysteine analogs selectively suppress pan-coronavirus replication by inhibition of nsp14 methyltransferase.

ABSTRACT: To address the ongoing threat of SARS-CoV-2 and potential emergence of novel coronaviruses, we employed a comprehensive strategy to identify and synthesize inhibitors of coronavirus methyltransferases with chemical analogs of S-adenosylhomocysteine. Two analogs, designated 4h and 4p, inhibit both mouse hepatitis virus and SARS-CoV-2 replication. Compound 4p was most potent with half-maximal inhibition of biochemical activity at 0.2 μM and antiviral activity at ~20 μM. This compound also has low cytotoxicity and preferentially inhibits nsp14 over nsp16 and human methyltransferases. Furthermore, molecular docking based on a newly determined crystal structure of the apo nsp16-nsp10 complex predicts 4p occupies both the S-adenosylmethione and Gppp bind

SUBMITTER: Rosas-Lemus M 

PROVIDER: S-EPMC12818953 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature