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Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening |
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| Author: | Roy, Anu1; Alhammad, Yousef M.2; McDonald, Peter1; |
| Organizations: |
1Infectious Disease Assay Development Laboratory/HTS, University of Kansas, Lawrence, KS, 66047, USA 2Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA 3Molecular Graphics and Modeling Laboratory and the Computational Chemical Biology Core, University of Kansas, Lawrence, KS, 66047, USA
4Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA
5Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland 6McDaniel College Department of Chemistry, 2 College Hill, Westminster, MD, USA 7McKusick-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 |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 6.7 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2023020225594 |
| Language: | English |
| Published: |
Elsevier,
2022
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| Publish Date: | 2023-02-02 |
| Description: |
AbstractThe 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. see all
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| Series: |
Antiviral research |
| ISSN: | 0166-3542 |
| ISSN-E: | 1872-9096 |
| ISSN-L: | 0166-3542 |
| Volume: | 203 |
| Article number: | 105344 |
| DOI: | 10.1016/j.antiviral.2022.105344 |
| OADOI: | https://oadoi.org/10.1016/j.antiviral.2022.105344 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
1182 Biochemistry, cell and molecular biology |
| Subjects: | |
| Funding: |
This research was funded by National Institutes of Health (NIH) grants P20 GM113117, P30GM110761, a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (#UL1TR002366), and University of Kansas start-up funds to ARF, and by Sidrid Jusélius foundation grant to LL, and Johns Hopkins Bloomberg School of Public Health Discretionary Fund to AKLL. DVF would like to acknowledge McDaniel College Student-Faculty Summer Research Fund, the Jean Richards Fund, the Schofield fund, and the Scott and Natalie Dahne fund. |
| Copyright information: |
© 2022 Elsevier B.V. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |