CDI-45205 for COVID-19

The three-year COVID-19 pandemic ‘has’ caused a wide range of medical, social, political, and financial implications. Since the end of 2020, various mutations and variations in SARS-CoV-2 strains, along with the immune escape phenomenon, have emerged. There is an urgent need to identify a relatively stable target for the development of universal vaccines and drugs that can effectively combat both SARS-CoV-2 strains and their mutants. Currently, the main focus in treating SARS-CoV-2 lies in disrupting the virus’s life cycle. The main protease (Mpro) is closely associated with virus replication and maturation and plays a crucial role in the early stages of infection. Consequently, it has become an important target for the development of SARS-CoV-2-specific drugs. This review summarizes the recent research progress on the novel coronavirus’s main proteases, including the pivotal role of Mpro in the virus’s life cycle, the structure and catalytic mechanism of Mpro, the self-maturation mechanism of Mpro, the role of Mpro in virus immune escape, the current methods of developing antiviral drugs targeting Mpro, and the key drugs that have successfully entered clinical trials. The aim is to provide researchers involved in the development of antiviral drugs targeting Mpro with systematic and comprehensive information.

Abstract Coronaviruses constitute a significant threat to the human population. Severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, is a highly pathogenic human coronavirus that has caused the coronavirus disease 2019 (COVID-19) pandemic. It has led to a global viral outbreak with an exceptional spread and a high death toll, highlighting the need for effective antiviral strategies. 3-Chymotrypsin-like protease (3CLpro), the main protease in SARS-CoV-2, plays an indispensable role in the SARS-CoV-2 viral life cycle by cleaving the viral polyprotein to produce 11 individual non-structural proteins necessary for viral replication. 3CLpro is one of two proteases that function to produce new viral particles. It is a highly conserved cysteine protease with identical structural folds in all known human coronaviruses. Inhibitors binding with high affinity to 3CLpro will prevent the cleavage of viral polyproteins, thus impeding viral replication. Multiple strategies have been implemented to screen for inhibitors against 3CLpro, including peptide-like and small molecule inhibitors that covalently and non-covalently bind the active site, respectively. In addition, allosteric sites of 3CLpro have been identified to screen for small molecules that could make non-competitive inhibitors of 3CLpro. In essence, this review serves as a comprehensive guide to understanding the structural intricacies and functional dynamics of 3CLpro, emphasizing key findings that elucidate its role as the main protease of SARS-CoV-2. Notably, the review is a critical resource in recognizing the advancements in identifying and developing 3CLpro inhibitors as effective antiviral strategies against COVID-19, some of which are already approved for clinical use in COVID-19 patients.