Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening.
Anu RoyYousef M O AlhammadPeter McDonaldDavid K JohnsonJunlin ZhuoSarah WazirDana V FerrarisLari LehtiöAnthony K L LeungAnthony R FehrPublished in: bioRxiv : the preprint server for biology (2022)
The emergence of several zoonotic viruses in the last twenty years, especially the pandemic outbreak of SARS-CoV-2, has exposed a dearth of antiviral drug therapies for viruses with pandemic potential. Developing a diverse drug portfolio will be critical for our ability to rapidly respond to novel coronaviruses (CoVs) and other viruses with pandemic potential. Here we focus on the SARS-CoV-2 conserved macrodomain (Mac1), a small domain of non-structural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that cleaves mono-ADP-ribose (MAR) from target proteins, protects the virus from the anti-viral effects of host ADP-ribosyltransferases, and is critical for the replication and pathogenesis of CoVs. In this study, a luminescent-based high-throughput assay was used to screen ∼38,000 small molecules for those that could inhibit Mac1-ADP-ribose binding. We identified 5 compounds amongst 3 chemotypes that inhibit SARS-CoV-2 Mac1-ADP-ribose binding in multiple assays with IC 50 values less than 100 µ M, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.
Keyphrases
- sars cov
- high throughput
- respiratory syndrome coronavirus
- binding protein
- single cell
- emergency department
- ms ms
- transcription factor
- liquid chromatography tandem mass spectrometry
- risk assessment
- gas chromatography mass spectrometry
- high resolution
- high performance liquid chromatography
- human health
- liquid chromatography
- solid phase extraction
- gas chromatography
- high resolution mass spectrometry