Arlo Loutan, University of Alberta

Arlo Loutan1, Adrien Delpal1, Emma Woolner1, and Matthias Götte1 1: Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta

Fighting & Responding

Influenza A viruses (IAVs) pose seasonal and pandemic threats to human health worldwide. Antiviral drugs targeting neuraminidase and the cap-snatching endonuclease are approved for use, though resistance-conferring mutations can lead to reduced susceptibility and breakthrough infections. Hence, alternative classes of antiviral drugs with limited cross-resistance are needed. The IAV polymerase complex contains a cap-binding domain in polymerase basic 2 protein (PB2), which is required for viral transcription. PB2 can be targeted by small molecules. Pimodivir is a first-generation cap-binding inhibitor, though its clinical development was halted. Onradivir, a second-generation cap-binding inhibitor, shows improved properties. Using recombinant polymerases, we observe that both pimodivir and onradivir are potent inhibitors of transcription against a range of IAV polymerases. Results have been confirmed in a minigenome assay, which further indicates that both compounds are effective against the polymerases of emerging H5 IAVs. In all cases, onradivir demonstrates improved IC50 values. Resistance-conferring PB2 F404Y and Q306H amino acid substitutions result in ~100-fold increase in IC50 values for both inhibitors, likely due to their shared scaffold. However, PB2 N510T leads to a 26-fold increase in IC50 for pimodivir versus a 2-fold increase for onradivir, which is a notable difference. Our results suggest that onradivir poses a higher barrier to resistance than pimodivir. Further clinical investigation is warranted for this promising class of antiviral drugs.