Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors.

ABSTRACT: The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the S-adenosyl-l-methionine and the RNA-binding site of SARS-CoV-2 nsp14 N⁷-methyltransferase. These hybrid molecules showed excellent potency, high selectivity toward various human methyltransferases, nontoxicity, and high cell permeability. Despite the outstanding activity against the enzyme, our compounds showed poor

SUBMITTER: Stefek M 

PROVIDER: S-EPMC10398685 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature