Structure-Activity Relationship Studies Towards Analogues of Pleconaril as Novel Enterovirus-D68 Capsid-Targeting Antivirals

Cousins, D. L.; Griffen, E. J.; Stacey, J.; Lee, A. A.; Filimonova, Y.; Hlavin, A.; Holota, Y.; Khmil, R.; Kordubailo, M.; Kostinov, O.; Lesyk, D.; Logvinenko, I.; Lototska, M.; Lysenko, V.; Pashchenko, A.; Pavlichenko, M.; Rodnichenko, A.; Tkachenko, A.; Hurst, B. L.; Julander, J. G.; Wang, H.; Pearl, R.; Benjamin, J.; Diaz-Tapia, R.; Gordon, M. E.; Albrecht, R. A.; White, K.

doi:10.1101/2025.08.08.668114

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bioRxiv · 10.1101/2025.08.08.668114

Structure-Activity Relationship Studies Towards Analogues of Pleconaril as Novel Enterovirus-D68 Capsid-Targeting Antivirals

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Abstract

Non-polio enteroviruses (NPEV) such as enterovirus D68 (EV-D68) that are highly infectious and associated with polio-like neurological complications have caused out-breaks, globally, in recent years. While some clinical and preclinical compounds have shown efficacy against NPEV in-vitro, liabilities that caused historical compounds such as pleconaril to fall short of FDA approval still remain. We present herein SAR and SPR studies of analogues of clinical compounds such as pleconaril and vapendavir against EV-D68 as a representative NPEV. Numerous structurally differentiated analogues with EV-D68 antiviral activity and useful ADME properties were discovered, which could serve as starting points for future EV drug discovery campaigns. Screening against a panel of enteroviruses revealed moderately broad-spectrum anti-EV activity of compound 26.

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Cousins, D. L., Griffen, E. J., Stacey, J., Lee, A. A., Filimonova, Y., Hlavin, A., Holota, Y., Khmil, R., Kordubailo, M., Kostinov, O., Lesyk, D., Logvinenko, I., Lototska, M., Lysenko, V., Pashchenko, A., Pavlichenko, M., Rodnichenko, A., Tkachenko, A., Hurst, B. L., Julander, J. G., Wang, H., Pearl, R., Benjamin, J., Diaz-Tapia, R., Gordon, M. E., Albrecht, R. A., White, K.. 2025-08-11. Structure-Activity Relationship Studies Towards Analogues of Pleconaril as Novel Enterovirus-D68 Capsid-Targeting Antivirals. https://doi.org/10.1101/2025.08.08.668114

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