Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain.

ABSTRACT: A series of amino acid based 7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to discern the structure activity relationships against the SARS-CoV-2 nsp3 macrodomain (Mac1), an ADP-ribosylhydrolase that is critical for coronavirus replication and pathogenesis. Structure activity studies identified compound 15c as a low-micromolar inhibitor of Mac1 in two ADP-ribose binding assays. This compound also demonstrated inhibition in an enzymatic assay of Mac1 and displayed a thermal shift comparable to ADPr in the melting temperature of Mac1 supporting binding to the target protein. A structural model reproducibly predicted a binding mode where the pyrrolo pyrimidine forms a hydrogen bonding network with Asp²² and the amide backbone NH of Ile²³ in the adenosine bin

SUBMITTER: Sherrill LM 

PROVIDER: S-EPMC9093066 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature