Orally Efficacious Broad-Spectrum Allosteric Inhibitor of Paramyxovirus Polymerase

Paramyxoviruses such as human parainfluenza virus type-3 (HPIV3) and measles virus (MeV) are a substantial health threat. In a high-throughput screen for inhibitors of HPIV3, a major cause of acute respiratory infection, we identified GHP-88309, a non-nucleoside inhibitor of viral polymerase activity that possesses unusual broad-spectrum activity against diverse paramyxoviruses including respiroviruses (i.e. HPIV1 and HPIV3) and morbilliviruses (i.e. MeV). Resistance profiles of distinct target viruses overlap spatially, revealing a conserved binding site in the central cavity of the viral polymerase (L) protein that was validated by photoaffinity labeling-based target mapping. Mechanistic characterization through viral RNA profiling and in vitro MeV polymerase assays identified a block in the initiation phase of the viral polymerase. GHP-88309 showed nanomolar potency against HPIV3 isolates in well-differentiated human airway organoid cultures, was well-tolerated (selectivity index >7,111), orally bioavailable, and provided complete protection against lethal infection in a Sendai virus (SeV)-mouse surrogate model of human HPIV3 disease when administered therapeutically 48 hours after infection. Recoverees had acquired robust immunoprotection against reinfection and viral resistance coincided with severe attenuation. This study provides proof-of-feasibility of a well-behaved broad-spectrum allosteric antiviral and describes a chemotype with high therapeutic potential that addresses major obstacles of anti-paramyxovirus drug development.