Research Progress of Antiviral Drug Targeting the Main Protease of SARS-CoV-2

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 in late 2019 posed a serious threat to the world population. Some effective vaccines are currently approved and widely used, but the long-term efficacy and safety of this intervention is controversial given the highly mutagenic nature of the coronavirus. In addition, some antiviral drugs show better effects, but their safety and universality have not been supported by more data. Coronavirus main protease (3CL(pro)) is a special cysteine protease in the coronavirus family, responsible for processing viral polyproteins to produce yield mature non- structural proteins, which play an important role in the life cycle of coronaviruses and are highly conserved, and therefor is considered as a prominent target for antiviral drug. Strucure studies provide valuable insight into the function of this protease and structural basis of rational inhibitor design. This paper reviews the structure of SARS-CoV-2 3CL(pro) and the research progress of bright spot inhibitors targeting 3CLpro so far, and introduces binding mode and the structure-activity relationships of inhibitors and 3CL(pro) in detail. Additionally, we broadly examine available antiviral activity, ADMET and animal tests of these inhibitors.