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

doi:10.1021/acsinfecdis.9b00035

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 journal › Article › peer-review

4 Scopus citations

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 language	English (US)
Pages (from-to)	2014-2028
Number of pages	15
Journal	ACS Infectious Diseases
Volume	5
Issue number	12
DOIs	https://doi.org/10.1021/acsinfecdis.9b00035
State	Published - Dec 13 2019

Keywords

VEEV
alphaviruses
antiviral inhibitors
dibenzyl amines

ASJC Scopus subject areas

Infectious Diseases

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10.1021/acsinfecdis.9b00035

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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

Nguyen, TH, Haese, NN, Madadi, N, Sarkar, S, Bonin, K, Streblow, CE, Taft-Benz, S, Tower, NA, Rasmussen, L, Bostwick, R, Augelli-Szafran, CE, Suto, MJ, Morrison, TE, Defilippis, V, Heise, MT, Streblow, DN & Pathak, AK 2019, 'Studies on Dibenzylamines as Inhibitors of Venezuelan Equine Encephalitis Virus', ACS Infectious Diseases, vol. 5, no. 12, pp. 2014-2028. https://doi.org/10.1021/acsinfecdis.9b00035

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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.",

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AU - Bonin, Kiley

AU - Streblow, Cassilyn E.

AU - Taft-Benz, Sharon

AU - Tower, Nichole A.

AU - Rasmussen, Lynn

AU - Bostwick, Robert

AU - Augelli-Szafran, Corinne E.

AU - Suto, Mark J.

AU - Morrison, Thomas E.

AU - Defilippis, Victor

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AU - Streblow, Daniel N.

AU - Pathak, Ashish K.

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N2 - 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.

AB - 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.

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Studies on Dibenzylamines as Inhibitors of Venezuelan Equine Encephalitis Virus

Abstract

Keywords

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