Discovery of Novel Broad-Spectrum Coronavirus Mpro Inhibitors

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PROJECT 1 - ABSTRACT The goal of this project is to discover novel broad-spectrum coronavirus main protease (Mpro) inhibitors. We have already obtained promising first-generation Mpro inhibitors with desired potency and drug-like properties. The first-generation Mpro inhibitors are rapidly progressing to clinical development. In the current application, we will capitalize the success of the first-generation inhibitor to develop the second-generation inhibitor. In anticipation of future coronavirus emergence, the second-generation inhibitor will have (i) activities against viruses resistant to the first-generation inhibitor and (ii) a broader coverage against different coronaviruses. To achieve this goal, we will pursue three aims: (i) identify the antiviral spectrum of the first-generation Mpro inhibitor and evaluate the potential to induce resistance; (ii) discover and optimize a second-generation novel broad- spectrum Mpro inhibitor to anticipate potential resistance and future pandemics; and (iii) advance our second- generation broad-spectrum coronavirus Mpro inhibitor through preclinical development to deliver an IND-ready clinical candidate.