Highly potent antiviral drug candidates targeting SARS-CoV-2 nsp3 and nsp5

Faced with the repeated emergence of three major epidemics caused by coronaviruses over the past 20 years (SARS-CoV in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019), the development of novel antiviral treatments has become a critical public health priority. In this study, molecular modeling tools, including docking, virtual screening, and molecular dynamics, were combined with databases to identify potential inhibitors of SARS-CoV-2 non-structural proteins nsp3 and nsp5. High-throughput virtual screening of the ZINC15 database led to the identification of two promising small molecules, Amb929 and Amb701, targeting nsp3 and nsp5, respectively. In vitro assays confirmed that both compounds inhibited SARS-CoV-2 replication, with Amb929 demonstrating superior antiviral efficacy and lower cytotoxicity compared to Amb701. Using a human airway epithelium model, Amb929 exhibited strong antiviral activity, a high selectivity index, and significant inhibition of viral replication, highlighting its ex vivo potential as a promising candidate for the development of effective anti-coronavirus drugs.