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

这个项目的总体目标是结合药物化学，x射线晶体学，

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) of SARS-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 countries worldwide. WHO has declared COVID-19 a global pandemic in March 11, 2020. As of early June, SARS-2 has infected ~7 million people (confirmed cases) globally, including ~2 million cases in the US. These numbers are rapidly growing everyday. SARS-2 is highly contagious. While most patients (81%) infected with SARS-2 show relatively 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 underlying medical conditions. SARS-2 has caused ~400,000 deaths globally including >110,000 in the US (as of early June, 2020), which makes it one of the most dangerous pathogens in modern history. There is therefore a pressing need to find effective therapeutics and vaccines for SARS-2 infection. The main protease (Mpro) of SARS-2 is essential for the viral replication and therefore a drug target. Specific Aim 1 is to use ration inhibitor design, medicinal chemistry and structure-activity relationship (SAR) studies to find more potent inhibitors of SARS-2 Mpro. Specific Aim 2 is to perform enzyme inhibition, X-ray crystallographic and other biochemical/physical studies to characterize compounds made in Aim 1, which will be used to guide rational design and SAR studies in Aim 1 to find compounds with improved potency. Specific Aim 3 is to perform cytotoxicity and cellular antiviral activity testing of selected potent inhibitors of SARS-2 Mpro, in order to find non-cytotoxic, potent antiviral compound against SARS-2 and -1 infections. Success of this pilot project would lead to small-molecule inhibitors with improved potency that can strongly inhibit SARS-2 replication. In addition, X-ray crystallography and other biochemical/physical studies would reveal the inhibitor-Mpro interactions. These compounds would serve as novel pharmacological leads for further drug development targeting SARS-2 and other coronavirus infection.