PoMA-10: a dual-action antiviral disrupting SARS-CoV-2 Spike-ACE2 interaction and protecting lung tissue

This study aimed to identify small molecules that inhibit the binding of the SARS-CoV-2 Spike protein to its host receptor, angiotensin-converting enzyme 2 (ACE2), without impairing the enzymatic activity of ACE2. Such inhibitors may support the development of broad-spectrum antivirals and therapeutic strategies for emerging SARS-CoV-2 variants. Through extensive screening using both cell-free and cell-based assays, we identified phenoxy-methylaniline (PoMA) compounds as effective inhibitors of the SARS-CoV-2 Spike-ACE2 interaction. Among these, PoMA-10, featuring trifluoromethoxy and dimethylaniline moieties, exhibited the most potent inhibitory activity while preserving ACE2 enzymatic function. Computational modeling predicted direct binding of PoMA-10 to ACE2, which was corroborated by protein mobility shift assays. This was further substantiated by surface plasmon resonance analysis and molecular dynamics simulations, which confirmed the stable binding of PoMA-10 at an interface-adjacent site on ACE2 and the disruption of SARS-CoV-2 Spike-ACE2 interaction. In Vero cells, PoMA-10 significantly reduced infection by ancestral SARS-CoV-2 and the Delta and Gamma variants. Moreover, PoMA-10 alleviated lung epithelial cell damage and protected against lipopolysaccharide-induced lung injury in vivo. These findings demonstrate that PoMA-10 functions as a dual-action inhibitor blocking viral entry and protecting against lung injury, and highlight its potential as a therapeutic candidate in the management of COVID-19 and related pulmonary complications.