Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses

Colleen Jonsson, Xufeng Cao, Jasper Lee, Jon D. Gabbard, Yong Kyu Chu, Elizabeth Fitzpatrick, Justin Julander, Dong Hoon Chung, Jennifer Stabenow, Jennifer E. Golden

Research output: Contribution to journalArticle

Abstract

Currently, there are no licensed human vaccines or antivirals for treatment of or prevention from infection with encephalitic alphaviruses. Because epidemics are sporadic and unpredictable, and endemic disease is common but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we have continued development of ML336 to deliver a molecule with prophylactic and therapeutic potential that could be relevant for use in natural epidemics or deliberate release scenario for Venezuelan equine encephalitis virus (VEEV). We report findings from in vitro assessments of four analogs of ML336, and in vivo screening of three of these new derivatives, BDGR-4, BDGR-69 and BDGR-70. The optimal dosing for maximal protection was observed at 12.5 mg/kg/day, twice daily for 8 days. BDGR-4 was tested further for prophylactic and therapeutic efficacy in mice challenged with VEEV Trinidad Donkey (TrD). Mice challenged with VEEV TrD showed 100% and 90% protection from lethal disease when treated at 24 and 48 h post-infection, respectively. We also measured 90% protection for BDGR-4 in mice challenged with Eastern equine encephalitis virus. In additional assessments of BDGR-4 in mice alone, we observed no appreciable toxicity as evaluated by clinical chemistry indicators up to a dose of 25 mg/kg/day over 4 days. In these same mice, we observed no induction of interferon. Lastly, the resistance of VEEV to BDGR-4 was evaluated by next-generation sequencing which revealed specific mutations in nsP4, the viral polymerase.

Original languageEnglish (US)
Pages (from-to)25-34
Number of pages10
JournalAntiviral Research
Volume167
DOIs
StatePublished - Jul 1 2019

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Eastern equine encephalitis virus
Venezuelan Equine Encephalitis Viruses
Trinidad and Tobago
Equidae
Alphavirus
Endemic Diseases
Clinical Chemistry
Therapeutics
Infection
Interferons
Antiviral Agents
Disease Outbreaks
Vaccination
Vaccines
Public Health
Mutation
Population

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Virology

Cite this

Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses. / Jonsson, Colleen; Cao, Xufeng; Lee, Jasper; Gabbard, Jon D.; Chu, Yong Kyu; Fitzpatrick, Elizabeth; Julander, Justin; Chung, Dong Hoon; Stabenow, Jennifer; Golden, Jennifer E.

In: Antiviral Research, Vol. 167, 01.07.2019, p. 25-34.

Research output: Contribution to journalArticle

Jonsson, C, Cao, X, Lee, J, Gabbard, JD, Chu, YK, Fitzpatrick, E, Julander, J, Chung, DH, Stabenow, J & Golden, JE 2019, 'Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses', Antiviral Research, vol. 167, pp. 25-34. https://doi.org/10.1016/j.antiviral.2019.04.004
Jonsson, Colleen ; Cao, Xufeng ; Lee, Jasper ; Gabbard, Jon D. ; Chu, Yong Kyu ; Fitzpatrick, Elizabeth ; Julander, Justin ; Chung, Dong Hoon ; Stabenow, Jennifer ; Golden, Jennifer E. / Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses. In: Antiviral Research. 2019 ; Vol. 167. pp. 25-34.
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