Enteroviruses

An analog of a clinical stage compound pleconaril, with potent activity across these enteroviruses in vitro was identified. We have demonstrated EV68, EV71, Polio, CVB3, CVB5 and Echovirus activities. We have also generated in vivo data for EV68 and CVB5. Our lead candidate is 10x more potent than pleconaril vs EV68 in vitro with no apparent CYP3A4 induction. This compound has demonstrated in vivo efficacy in a 5 day mouse model provided by NIAID. 

Recent studies by several research groups have demonstrated enterovirus infection in the pancreas of newly diagnosed type I diabetes (T1D) patients and therefore a strong association with this disease. A clinical trial recently showed that pleconaril and ribavirin can significantly increase serum C-peptide versus placebo, suggesting the potential to preserve insulin production in patients with T1D. Our lead candidate may have applications for T1D and other diseases.

Lane TR, Fu J, Sherry B, Tarbet B, Hurst BL, Riabova O, Kazakova E, Egorova A, Clarke P, Leser JS, Frost J, Rudy M, Tyler KL, Klose T, Volobueva AS, Belyaevskaya SV, Zarubaev VV, Kuhn RJ, Makarov V, Ekins S. Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5. Antiviral Res. 2023 Aug;216:105654

Volobueva A, Egorova A, Galochkina A, Ekins S, Zarubaev V, Makarov V. The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have Biological Activity towards Coxsackievirus B3 Nancy. Molecules. 2020 Mar 16;25(6):1345

Egorova A, Kazakova E, Jahn B, Ekins S, Makarov V, Schmidtke M. Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses. Eur J Med Chem. 2020 Feb 15;188:112007

Egorova A, Ekins S, Schmidtke M, Makarov V. Back to the future: Advances in development of broad-spectrum capsid-binding inhibitors of enteroviruses. Eur J Med Chem. 2019 Sep 15;178:606-622