Studies on Dibenzylamines as Inhibitors of Venezuelan Equine Encephalitis Virus

Theresa H. Nguyen, Nicole N. Haese, Nikhil Madadi, Sanjay Sarkar, Kiley Bonin, Cassilyn E. Streblow, Sharon Taft-Benz, Nichole A. Tower, Lynn Rasmussen, Robert Bostwick, Corinne E. Augelli-Szafran, Mark J. Suto, Thomas E. Morrison, Victor Defilippis, Mark T. Heise, Daniel N. Streblow, Ashish K. Pathak

Research output: Contribution to journalArticle

Abstract

Alphaviruses are arthropod-transmitted members of the Togaviridae family that can cause severe disease in humans, including debilitating arthralgia and severe neurological complications. Currently, there are no approved vaccines or antiviral therapies directed against the alphaviruses, and care is limited to treating disease symptoms. A phenotypic cell-based high-throughput screen was performed to identify small molecules that inhibit the replication of Venezuelan Equine Encephalitis Virus (VEEV). The compound, 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(3-fluoro-4-methoxybenzyl)ethan-1-amine (1), was identified as a highly active, potent inhibitor of VEEV with an effective concentration for 90% inhibition of virus (EC90) of 0.89 μM and 7.49 log reduction in virus titers at 10 μM concentration. These data suggest that further investigation of compound 1 as an antiviral therapeutic against VEEV, and perhaps other alphaviruses, is warranted. Experiments suggested that the antiviral activity of compound 1 is directed at an early step in the VEEV replication cycle by blocking viral RNA and protein synthesis.

Original languageEnglish (US)
Pages (from-to)2014-2028
Number of pages15
JournalACS Infectious Diseases
Volume5
Issue number12
DOIs
StatePublished - Dec 13 2019

Keywords

  • VEEV
  • alphaviruses
  • antiviral inhibitors
  • dibenzyl amines

ASJC Scopus subject areas

  • Infectious Diseases

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    Nguyen, T. H., Haese, N. N., Madadi, N., Sarkar, S., Bonin, K., Streblow, C. E., Taft-Benz, S., Tower, N. A., Rasmussen, L., Bostwick, R., Augelli-Szafran, C. E., Suto, M. J., Morrison, T. E., Defilippis, V., Heise, M. T., Streblow, D. N., & Pathak, A. K. (2019). Studies on Dibenzylamines as Inhibitors of Venezuelan Equine Encephalitis Virus. ACS Infectious Diseases, 5(12), 2014-2028. https://doi.org/10.1021/acsinfecdis.9b00035