 The study reports the development and preclinical evaluation of an orally bioavailable SARS-CoV-2-3-C, like proteins, 3Cl-PRO inhibitor, synotrelvia, which covalently inhibits SARS-CoV-2-3-Cl-PRO with high selectivity and effectively blocks replications of SARS-CoV-2 variants in cell-based assays. Synotrelvia exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2-Delta infection. The discovery of synotrelvia highlights the utility of structure-based development of mark-protease inhibitors for providing a small molecule therapeutic effectively combating human coronaviruses. This article was authored by Shangrui Jiang, Haishesu, Wei Huan-Xiong, and others.