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

Lavinia M Sherrill; Elva E Joya; AnnMarie Walker; Anuradha Roy; Yousef M Alhammad; Moriama Atobatele; Sarah Wazir; George Abbas; Patrick Keane; Junlin Zhuo; Anthony K L Leung; David K Johnson; Lari Lehtiö; Anthony R Fehr; Dana Ferraris

doi:10.1016/j.bmc.2022.116788

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

Bioorg Med Chem. 2022 Aug 1:67:116788. doi: 10.1016/j.bmc.2022.116788. Epub 2022 May 11.

Authors

Affiliations

¹ McDaniel College, Department of Chemistry, 2 College Hill, Westminster, MD 21157, USA.
² Infectious Disease Assay Development Laboratory/HTS, University of Kansas, Lawrence, KS 66047, USA.
³ Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
⁴ Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.
⁵ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁶ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, McKusick-Nathans Department of Genetic Medicine and Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
⁷ Molecular Graphics and Modeling Laboratory and the Computational Chemical Biology Core, University of Kansas, Lawrence, KS 66047, USA.
⁸ Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA. Electronic address: arfehr@ku.edu.
⁹ McDaniel College, Department of Chemistry, 2 College Hill, Westminster, MD 21157, USA. Electronic address: dferraris@mcdaniel.edu.

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 binding pocket and the carboxylate forms hydrogen bonds to the amide backbone of Phe¹⁵⁷ and Asp¹⁵⁶, part of the oxyanion subsite of Mac1. Compound 15c also demonstrated notable selectivity for coronavirus macrodomains when tested against a panel of ADP-ribose binding proteins. Together, this study identified several low MW, low µM Mac1 inhibitors to use as small molecule chemical probes for this potential anti-viral target and offers starting points for further optimization.

Keywords: ADP-ribosylation; COVID-19; Coronavirus; Nsp3 macrodomain inhibitors; SARS-CoV-2.

Publication types

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

MeSH terms

Adenosine Diphosphate Ribose / metabolism
Amides
COVID-19 Drug Treatment*
Humans
Protein Domains
SARS-CoV-2*

Substances

Amides
Adenosine Diphosphate Ribose

Abstract

Publication types

MeSH terms

Substances

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