Discovery of meisoindigo derivatives as noncovalent and orally available M inhibitors: their therapeutic implications in the treatment of COVID-19.

The progressive emergence of SARS-CoV-2 variants has necessitated the urgent exploration of novel therapeutic strategies to combat the COVID-19 pandemic. The SARS-CoV-2 main protease (M) represents an evolutionarily conserved therapeutic target for drug discovery. This study highlights the discovery of meisoindigo (Mei), derived from the traditional Chinese medicine (TCM) Indigo naturalis, as a novel non-covalent and nonpeptidic M inhibitor. Substantial optimizations and structure-activity relationship (SAR) studies, guided by a structure-based drug design approach, led to the identification of several Mei derivatives, including S5-27 and S5-28, exhibiting low micromolar inhibition against SARS-CoV-2 M with high binding affinity. Notably, S5-28 provided significant protection against wild-type SARS-CoV-2 in HeLa-hACE2 cells, with EC up to 2.66 μM. Furthermore, it displayed favorable physiochemical properties and remarkable gastrointestinal and metabolic stability, demonstrating its potential as an orally bioavailable drug for anti-COVID-19 therapy. This research presents a promising avenue for the development of new antiviral agents, offering hope in the ongoing battle against COVID-19.