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: Across the globe, countries are being challenged by the SARS-CoV-2 (COVID-19) pandemic in ways they have never been before. Global outbreak of SARS-CoV-2 with an uncertain fatality rate has imposed extreme challenges on global health. The World Health Organization (WHO) has officially declared the outbreak of COVID-19 a pandemic, after the disease caused by the new coronavirus spread to more than 100 countries. To date, various therapeutic approaches has been proposed and are being implemented to combat this pandemic, but unfortunately, no sovereign remedy has been es-tablished yet. Protease enzymes are important targets to develop therapies for the treatment of infections caused by SARS coronaviruses. In this review, an overview is given on recent advances in discovery of potent protease inhibitors targeting the SARS coronaviruses. Different classes of natural product inhibitors targeting protease enzymes of SARS coronaviruses have been studied in detail along with their structure activity relationship analysis. This study emphasized on important covalent and non-covalent small molecule inhibitors which effectively inhibited chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) of two SARS coronaviruses i.e. SARS-CoV-1 and SARS-CoV-2. Repurposing of drugs has been also outlined in this study to understand their roles as quick-to-be-identified therapy to combat these zoonotic coronaviruses.

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