Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5

• Published in: Antiviral research Vol. 216; p. 105654
• Main Authors: Lane, Thomas R., Fu, Jianing, Sherry, Barbara, Tarbet, Bart, Hurst, Brett L., Riabova, Olga, Kazakova, Elena, Egorova, Anna, Clarke, Penny, Leser, J. Smith, Frost, Joshua, Rudy, Michael, Tyler, Kenneth L., Klose, Thomas, Volobueva, Alexandrina S., Belyaevskaya, Svetlana V., Zarubaev, Vladimir V., Kuhn, Richard J., Makarov, Vadim, Ekins, Sean
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2023
• Subjects: Antiviral; Coxsackievirus B5; Cryo-electron microscopy; Enteroviruses; EV-D68; Coxsackievirus B5; Enteroviruses; Antiviral; EV-D68; Cryo-electron microscopy
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2023.105654

Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. There is no antiviral treatment available for either. We have developed an isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of EV-D68 (IC50 58 nM) as well as other enteroviruses including the pleconaril-resistant Coxsackievirus B3-Woodruff (IC50 6–20 nM) and CVB5 (EC50 1 nM). Cryo-electron microscopy structures of EV-D68 in complex with 11526092 and pleconaril demonstrate destabilization of the EV-D68 MO strain VP1 loop, and a strain-dependent effect. A mouse respiratory model of EV-D68 infection, showed 3-log decreased viremia, favorable cytokine response, as well as statistically significant 1-log reduction in lung titer reduction at day 5 after treatment with 11526092. An acute flaccid myelitis neurological infection model did not show efficacy. 11526092 was tested in a mouse model of CVB5 infection and showed a 4-log TCID50 reduction in the pancreas. In summary, 11526092 represents a potent in vitro inhibitor of EV with in vivo efficacy in EV-D68 and CVB5 animal models suggesting it is worthy of further evaluation as a potential broad-spectrum antiviral therapeutic against EV. [Display omitted] •Enterovirus-D68 (EV-D68) and Coxsackie B5 (CVB5) have no approved treatment.•Our lead molecule 11526092 demonstrates protein destabilization by Cryo-EM.•11526092 displays in vitro potency against multiple enteroviruses.•11526092 also displays in vivo efficacy against EV-D68 and CVB5.•11526092 represents a future treatment for EV-D68, CVB5 and other enteroviruses.