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SARS-CoV-2 Nsp15 endoribonuclease

ABSTRACT: The emergence of SARS-CoV-2, the causative agent of COVID-19, has resulted in the largest pandemic in recent history. Current therapeutic strategies to mitigate this disease have focused on the development of vaccines and on drugs that inhibit the viral 3CL protease or RNA-dependent RNA polymerase enzymes. A less- explored and potentially complementary drug target is Nsp15, a uracil-specific RNA endonuclease that shields coronaviruses and other nidoviruses from mammalian innate immune defenses. Here, we perform a high-throughput screen of over 100,000 small molecules to identify Nsp15 inhibitors. We characterize the potency, mechanism, selectivity, and predicted binding mode of five lead compounds. We show that one of these, IPA-3, is a covalent inhibitor that modifies two key Cys residues (Cys291 and Cys293) within the catalytic core of Nsp15 that are implicated in activity. Moreover, we demonstrate that three of these inhibitors (Hexachlorophene, IPA-3, and CID5675221) block SARS-CoV-2 replication in cells at subtoxic doses. This study provides a pipeline for the identification of Nsp15 inhibitors, and pinpoints lead compounds for further development against COVID-19 and related coronavirus infections.

INSTRUMENT(S): Q Exactive orbitrap mass spectrometer

ORGANISM(S): Sars Coronavirus (ncbitaxon:227859)

SUBMITTER: Basil Hubbard

PROVIDER: MSV000092541 | MassIVE | Thu Jul 27 11:55:00 BST 2023

REPOSITORIES: MassIVE

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