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TitleEfficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5.
Journal, issue, pagesAntiviral Res, Vol. 216, Page 105654, Year 2023
Publish dateJun 14, 2023
AuthorsThomas R Lane / Jianing Fu / Barbara Sherry / Bart Tarbet / Brett L Hurst / Olga Riabova / Elena Kazakova / Anna Egorova / Penny Clarke / J Smith Leser / Joshua Frost / Michael Rudy / Kenneth L Tyler / Thomas Klose / Alexandrina S Volobueva / Svetlana V Belyaevskaya / Vladimir V Zarubaev / Richard J Kuhn / Vadim Makarov / Sean Ekins /
PubMed AbstractEnteroviruses (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) ...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.
External linksAntiviral Res / PubMed:37327878 / PubMed Central
MethodsEM (single particle)
Resolution2.0 - 2.7 Å
Structure data

25765

7t9p

EMDB-25765, PDB-7t9p:
Cryo-EM structure of Human Enterovirus D68 US/MO/14-18947 strain native virion
Method: EM (single particle) / Resolution: 2.0 Å

25772

7taf

EMDB-25772, PDB-7taf:
Cryo-EM structure of Human Enterovirus D68 US/MO/14-18947 strain virion in complex with inhibitor 11526092
Method: EM (single particle) / Resolution: 2.0 Å

25773

7tag

EMDB-25773, PDB-7tag:
Cryo-EM structure of Human Enterovirus D68 US/MO/14-18947 strain virion in complex with pleconaril
Method: EM (single particle) / Resolution: 2.7 Å

25774

7tah

EMDB-25774, PDB-7tah:
Cryo-EM structure of Human Enterovirus D68 US/MO/14-18947 strain in complex with inhibitor 11526091 (no/low occupancy-no inhibitor modeled)
Method: EM (single particle) / Resolution: 2.3 Å

25776

7taj

EMDB-25776, PDB-7taj:
Cryo-EM structure of Human Enterovirus D68 US/MO/14-18947 strain in complex with inhibitor 11526093 (no/low occupancy-no inhibitor modeled)
Method: EM (single particle) / Resolution: 2.0 Å

Chemicals

ChemComp-GFI:
N,N-dimethyl-5-(3-{2-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,2-oxazole-3-carboxamide

ChemComp-W11:
3-{3,5-DIMETHYL-4-[3-(3-METHYL-ISOXAZOL-5-YL)-PROPOXY]-PHENYL}-5-TRIFLUOROMETHYL-[1,2,4]OXADIAZOLE / antivirus*YM

Source
  • enterovirus d68
KeywordsVIRUS / EV-D68 / acute flaccid myelitis / AFM / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID / VIRUS/INHIBITOR / inhibitor / antiviral / VIRUS-INHIBITOR complex / antivirial

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