The paramyxovirus family contains some of the most contagious airborne viral pathogens identified to date. Recently emerged zoonotic family members such as deadly Nipah virus of the henipavirus genus and newly emerging bat morbilliviruses pose a major health threat that could develop into a catastrophic global pandemic if the ability for efficient human-to-human transmission is acquired post-zoonosis. AC/DC project 3 will meet this challenge through the development of nucleoside analog and allosteric antivirals targeting the paramyxovirus polymerase complex. In collaboration of the Lee, Plemper, and Freiberg laboratories, project 3 will optimize existing assets with confirmed anti-paramyxovirus activity against the henipavirus and bat morbillivirus target. Building on these exciting hit candidates, project 3 will liaise closely with AC/DC scientific cores for lead development and characterization, and explore novel anti-rubulavirus chemotypes with the AC/DC HTS core.
EIDD-2749 and GHP-88309 are exemplar NRPI and NNRPI chemotypes that are orally bioavailable, active against multiple genera of PMVs, have a wide safety margin (SI>500), favorable PK that allow for one or twice daily dosing and have nonoverlapping and fitness limiting resistance profiles. Specific Aims 1 and 2 will develop exemplar NRPI and NNRPI as henipavirus inhibitors using a suite of in vitro and in vivo de-risking studies. Specific Aim 3 will target morbilliviruses using GHP-88309 and ERDRP-0519. The latter is a well characterized NNRPI specific for morbilliviruses that has shown oral bioefficacy in animal models. Specific Aim 4 will target emerging bat rubulaviruses by performing a full-scale HTS using recombinant Menangle virus (MenV), and subjecting putative hits to our hit-to-lead developmental cascade.