Novel small-molecule inhibitors of SARS-CoV-2 protease

The overall objective of this project is to use a combination of medicinal chemistry, X-ray crystallography,biochemical and biological activity testing to develop potent, drug-like inhibitors of the main protease (Mpro) ofSARS-CoV-2 (SARS-2), a novel coronavirus that causes an outbreak of a serious pulmonary disease COVID-19 (coronavirus disease 2019). SARS-2 has emerged in Wuhan, China and soon spread to >210 countriesworldwide. WHO has declared COVID-19 a global pandemic in March 11, 2020. As of early June, SARS-2 hasinfected ~7 million people (confirmed cases) globally, including ~2 million cases in the US. These numbers arerapidly growing everyday. SARS-2 is highly contagious. While most patients (81%) infected with SARS-2 showrelatively mild symptoms, life-threatening severe illness, including severe pneumonia, sepsis and organ failure,can occur at a significantly higher risk for people at age of ≥65 years and people with serious underlyingmedical conditions. SARS-2 has caused ~400,000 deaths globally including >110,000 in the US (as of earlyJune, 2020), which makes it one of the most dangerous pathogens in modern history. There is therefore apressing need to find effective therapeutics and vaccines for SARS-2 infection. The main protease (Mpro) ofSARS-2 is essential for the viral replication and therefore a drug target. Specific Aim 1 is to use ration inhibitordesign, medicinal chemistry and structure-activity relationship (SAR) studies to find more potent inhibitors ofSARS-2 Mpro. Specific Aim 2 is to perform enzyme inhibition, X-ray crystallographic and otherbiochemical/physical studies to characterize compounds made in Aim 1, which will be used to guide rationaldesign and SAR studies in Aim 1 to find compounds with improved potency. Specific Aim 3 is to performcytotoxicity and cellular antiviral activity testing of selected potent inhibitors of SARS-2 Mpro, in order to findnon-cytotoxic, potent antiviral compound against SARS-2 and -1 infections. Success of this pilot project wouldlead to small-molecule inhibitors with improved potency that can strongly inhibit SARS-2 replication. Inaddition, X-ray crystallography and other biochemical/physical studies would reveal the inhibitor-Mprointeractions. These compounds would serve as novel pharmacological leads for further drug developmenttargeting SARS-2 and other coronavirus infection.