Discovery of meisoindigo derivatives as noncovalent and orally available Mpro 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 (Mpro) 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 Mpro 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 Mpro with high binding affinity. Notably, S5-28 provided significant protection against wild-type SARS-CoV-2 in HeLa-hACE2 cells, with EC50 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. In this work, Meisoindigo was identified as a novel nonpeptidic and non-covalent Mpro inhibitor. With Mei as the lead compound, more than 30 derivatives were designed, synthesized. Among them, S5-28 not only exhibited potent Mpro inhibitory and anti-SARS-CoV-2 activity, but also demonstrated favorable physiochemical properties and stabilities, suggesting its therapeutic potential as an orally bioavailable anti-viral agent. [Display omitted] •Indigo naturalis-derived Meisoindigo was identified as a novel non-peptidic and non-covalent SARS-CoV-2 Mpro inhibitor.•More than 30 Mei derivatives were designed, synthesized and screened to elucidate SARs.•S5-28 showed potent anti-SARS-CoV-2 activity and favorable physiochemical properties and stabilities.