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

Anu Roy; Yousef M Alhammad; Peter McDonald; David K Johnson; Junlin Zhuo; Sarah Wazir; Dana Ferraris; Lari Lehtiö; Anthony K L Leung; Anthony R Fehr

doi:10.1016/j.antiviral.2022.105344

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. Epub 2022 May 19.

Authors

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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adenosine Diphosphate Ribose / metabolism
COVID-19 Drug Treatment*
High-Throughput Screening Assays
Humans
SARS-CoV-2*
Viral Nonstructural Proteins / chemistry

Substances

Viral Nonstructural Proteins
Adenosine Diphosphate Ribose

Abstract

Publication types

MeSH terms

Substances

Grants and funding