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Perspective

The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses

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Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
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Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
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McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
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Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
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W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
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Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA
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InterRayBio, LLC, Cleveland, OH 44106, USA
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Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
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Authors to whom correspondence should be addressed.
Academic Editor: Luis Martinez-Sobrido
Pathogens 2022, 11(1), 94; https://doi.org/10.3390/pathogens11010094
Received: 22 December 2021 / Revised: 7 January 2022 / Accepted: 11 January 2022 / Published: 14 January 2022
(This article belongs to the Special Issue ADP-Ribosylation in Pathogens)
Emerging and re-emerging viral diseases pose continuous public health threats, and effective control requires a combination of non-pharmacologic interventions, treatment with antivirals, and prevention with vaccines. The COVID-19 pandemic has demonstrated that the world was least prepared to provide effective treatments. This lack of preparedness has been due, in large part, to a lack of investment in developing a diverse portfolio of antiviral agents, particularly those ready to combat viruses of pandemic potential. Here, we focus on a drug target called macrodomain that is critical for the replication and pathogenesis of alphaviruses and coronaviruses. Some mutations in alphavirus and coronaviral macrodomains are not tolerated for virus replication. In addition, the coronavirus macrodomain suppresses host interferon responses. Therefore, macrodomain inhibitors have the potential to block virus replication and restore the host’s protective interferon response. Viral macrodomains offer an attractive antiviral target for developing direct acting antivirals because they are highly conserved and have a structurally well-defined (druggable) binding pocket. Given that this target is distinct from the existing RNA polymerase and protease targets, a macrodomain inhibitor may complement current approaches, pre-empt the threat of resistance and offer opportunities to develop combination therapies for combating COVID-19 and future viral threats. View Full-Text
Keywords: coronavirus; alphavirus; SARS-CoV-2; macrodomain; ADP-ribosylation; ADP-ribosylhydrolase; therapeutics coronavirus; alphavirus; SARS-CoV-2; macrodomain; ADP-ribosylation; ADP-ribosylhydrolase; therapeutics
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MDPI and ACS Style

Leung, A.K.L.; Griffin, D.E.; Bosch, J.; Fehr, A.R. The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses. Pathogens 2022, 11, 94. https://doi.org/10.3390/pathogens11010094

AMA Style

Leung AKL, Griffin DE, Bosch J, Fehr AR. The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses. Pathogens. 2022; 11(1):94. https://doi.org/10.3390/pathogens11010094

Chicago/Turabian Style

Leung, Anthony K.L., Diane E. Griffin, Jürgen Bosch, and Anthony R. Fehr. 2022. "The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses" Pathogens 11, no. 1: 94. https://doi.org/10.3390/pathogens11010094

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