Dr. Dan Talley
National Institutes of Health (NIH)
Friday, October 17, 2025
12:00 Noon
Room 120 – Meyerhoff Chemistry Building
Host: Dr. Paul Smith
“Advancing Rabies Antiviral Research: A Multi-Platform Screening and Optimization Approach Utilizing 3D-Neural Models”
Rabies virus (RABV) infection is preventable via prophylactic vaccination and curable only if treated quickly, with a combination of human Rabies immunoglobulin (HRIG) and multiple doses of vaccine. However, HRIG remains widely unavailable in the developing world and the cost of treatment is drastically increasing. To address these shortcomings, a quantitative high-throughput screen (qHTS) of ~30k small molecules was performed using a target-agnostic, live-virus assay. qHTS results guided an in silico screen of an additional ~42k compounds utilizing AI-driven QSAR and pharmacophore modeling. Subsequent medicinal chemistry optimization of a novel hit chemotype yielded a potent probe with < 100 nM activity and a favorable pharmacokinetic profile in mice and hamsters. Efficacy was further evaluated in two human-derived, 3D-organoid and tissue models, which mimic CNS-relevant viral infection. The optimized small molecule inhibitor has strong antiviral activity and low cytotoxicity in these surrogate models of efficacy, supporting its utility as a promising lead for further in vivo therapeutic testing and development.