Discovery of RdRp Thumb-1 as a novel broad-spectrum antiviral family of targets and MDL-001 as a potent broad-spectrum inhibitor thereof

Multiple positive-sense, single-stranded RNA (+ssRNA) viruses cause human diseases, ranging from mild colds to deadly pandemics. These viruses share a highly conserved RNA-dependent RNA polymerase (RdRp), but developing a non-nucleoside RdRp inhibitor with broad antiviral activity has been elusive. To this end, we first compared RdRp structures across +ssRNA viral families, including homology models created for critical viruses lacking solved crystal structures. We used multiple sequence alignments to observe key loop and pocket residues. Second, we used ChemPrint, a Molecular-Geometric Deep Learning (Mol-GDL) machine learning model, to predict drug inhibition of the Thumb-1 site in RdRp in a panel of +ssRNA viruses of concern. We identified pipendoxifene (MDL-001) as a promising broad-spectrum antiviral that in previous clinical studies, has demonstrated safety and tolerability and sufficient evidence to support its oral administration and once-a-day dosing. These experiments also demonstrated how the Thumb-1 site has been hidden from conventional virtual screening techniques, like docking, and we demonstrated why beclabuvir, the only approved (Japan) Thumb-1 inhibitor, does not work as a broad-spectrum antiviral. Recent preclinical studies have demonstrated MDL-001 efficacy across multiple RNA virus families, reinforcing its therapeutic promise for undifferentiated viral infection.