Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 4, Pages 2716-2746Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01140
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Funding
- MIUR-Ministero dell'Istruzione, dell'Universita` e della Ricerca (Italian Ministry of Education, University and Research), PON R& I 2014-2020-AIM (Attraction and International Mobility) [AIM1873131]
- EU [101003551]
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This article discusses the urgent need to identify drugs for treating COVID-19 and other coronavirus diseases. Different strategies targeting the virus or host cells are being investigated. The article provides a comprehensive comparative analysis of SARS-CoV-2 proteases and RdRp with other coronavirus counterparts, highlighting the most promising inhibitors reported so far and potential strategies for further development.
The newly emerged coronavirus, called SARS-CoV-2, is the causing pathogen of pandemic COVID-19. The identification of drugs to treat COVID-19 and other coronavirus diseases is an urgent global need, thus different strategies targeting either virus or host cell are still under investigation. Direct-acting agents, targeting protease and polymerase functionalities, represent a milestone in antiviral therapy. The 3C-like (or Main) protease (3CL(Pro)) and the nsp12 RNA-dependent RNA-polymerase (RdRp) are the best characterized SARS-CoV-2 targets and show the highest degree of conservation across coronaviruses fostering the identification of broad-spectrum inhibitors. Coronaviruses also possess a papain-like protease, another essential enzyme, still poorly characterized and not equally conserved, limiting the identification of broad-spectrum agents. Herein, we provide an exhaustive comparative analysis of SARS-CoV-2 proteases and RdRp with respect to other coronavirus homologues. Moreover, we highlight the most promising inhibitors of these proteins reported so far, including the possible strategies for their further development.
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