7TAF

Cryo-EM structure of Human Enterovirus D68 US/MO/14-18947 strain virion in complex with inhibitor 11526092

Summary for 7TAF

• Entry DOI: 10.2210/pdb7taf/pdb
• EMDB information: 25772
• Descriptor: viral protein 1, viral protein 3, viral protein 2, ... (5 entities in total)
• Functional Keywords: virus, ev-d68, acute flaccid myelitis, afm, inhibitor, antiviral, structural genomics, center for structural genomics of infectious diseases, csgid, virus-inhibitor complex, virus/inhibitor
• Biological source: enterovirus D68; More
• Total number of polymer chains: 4
• Total formula weight: 94266.45

Authors

Fu, J.,Klose, T.,Kuhn, R.J.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2021-12-20, release date: 2023-01-25, Last modification date: 2026-03-25)

Primary citation

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

PubMed Abstract: 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 (IC 58 nM) as well as other enteroviruses including the pleconaril-resistant Coxsackievirus B3-Woodruff (IC 6-20 nM) and CVB5 (EC 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 TCID 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.

PubMed: 37327878
DOI: 10.1016/j.antiviral.2023.105654

Experimental method

ELECTRON MICROSCOPY (2 Å)