2. Academic Validation
  3. Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening

Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening

  • Antiviral Res. 2022 Jul:203:105344. doi: 10.1016/j.antiviral.2022.105344.
Anu Roy 1,  Yousef M Alhammad 2,  Peter McDonald 1,  David K Johnson 3,  Junlin Zhuo 4,  Sarah Wazir 5,  Dana Ferraris 6,  Lari Lehtiö 5,  Anthony K L Leung 7,  Anthony R Fehr 8
Affiliations

Affiliations

  • 1 Infectious Disease Assay Development Laboratory/HTS, University of Kansas, Lawrence, KS, 66047, USA.
  • 2 Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA.
  • 3 Molecular Graphics and Modeling Laboratory and the Computational Chemical Biology Core, University of Kansas, Lawrence, KS, 66047, USA.
  • 4 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA.
  • 5 Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.
  • 6 McDaniel College Department of Chemistry, 2 College Hill, Westminster, MD, USA.
  • 7 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA; McKusick-Nathans Department of Genetics Medicine, Department of Oncology, And Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
  • 8 Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA. Electronic address: arfehr@ku.edu.
PMID: 35598780 DOI: 10.1016/j.antiviral.2022.105344
Abstract

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 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 IC50 values less than 100 μM, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.

Keywords

ADP-Ribose; ADP-Ribosylation; Coronavirus; High-throughput screening; Macrodomain; SARS-CoV-2.

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