Abstract
The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (M pro ) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV M pro s. Crystal structures of M pro s from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of M pro s from other coronaviruses. In consideration of the important role of M pro in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral M pro inhibitors that are safer and more effective.
Keywords: YH-53; coronavirus; inhibitor; main protease; warhead.
【저자키워드】 coronavirus, main protease, inhibitor, warhead., YH-53, 【초록키워드】 COVID-19, Treatment, SARS-CoV-2, Coronaviruses, Vaccine, Antiviral, SARS-CoV, antivirals, variant, protease, MERS-CoV, Spread, Health, viral replication, molecular, crystal structure, mechanism, binding, Coronavirus-2, Analysis, determinant, acute respiratory syndrome, maturation, enzyme, other coronaviruses, M pro, effective inhibitor, effective, consequence, defined, caused, required, provide, unique, promote, 【제목키워드】 inhibition, Basis,