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Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3

1
National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, USA
2
DCE Consulting, Vienna, VA 22181, USA
3
School of Systems Biology, George Mason University, Manassas, VA 20110, USA
4
American Type Culture Collection, Manassas, VA 20110, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Cheng-Wen Lin and Szu-Hao Kung
Viruses 2021, 13(8), 1533; https://doi.org/10.3390/v13081533
Received: 28 June 2021 / Revised: 20 July 2021 / Accepted: 29 July 2021 / Published: 3 August 2021
(This article belongs to the Topic Broad-Spectrum Antiviral Agents)
Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV non-structural protein 3 (nsP3) facilitates cell-specific and virus-specific host factor binding preferences among alphaviruses, thereby providing targets of interest when designing novel antiviral therapeutics. In this study, we utilized an overexpression construct encoding HA-tagged nsP3 to identify host proteins that interact with VEEV nsP3 by mass spectrometry. Bioinformatic analyses of the putative interactors identified 42 small molecules with the potential to inhibit the host interaction targets, and thus potentially inhibit VEEV. Three inhibitors, tomatidine, citalopram HBr, and Z-VEID-FMK, reduced replication of both the TC-83 strain and the Trinidad donkey (TrD) strain of VEEV by at least 10-fold in astrocytoma, astroglial, and microglial cells. Further, these inhibitors reduced replication of the related New World (NW) alphavirus Eastern equine encephalitis virus (EEEV) in multiple cell types, thus demonstrating broad-spectrum antiviral activity. Time-course assays revealed all three inhibitors reduced both infectious particle production and positive-sense RNA levels post-infection. Further evaluation of the putative host targets for the three inhibitors revealed an interaction of VEEV nsP3 with TFAP2A, but not eIF2S2. Mechanistic studies utilizing siRNA knockdowns demonstrated that eIF2S2, but not TFAP2A, supports both efficient TC-83 replication and genomic RNA synthesis, but not subgenomic RNA translation. Overall, this work reveals the composition of the VEEV nsP3 proteome and the potential to identify host-based, broad spectrum therapeutic approaches to treat new world alphavirus infections. View Full-Text
Keywords: Venezuelan equine encephalitis virus; non-structural protein 3; host-proteome; small molecule inhibitors; mass spectrometry; viral proteome; eIF2S2; TFAP2A Venezuelan equine encephalitis virus; non-structural protein 3; host-proteome; small molecule inhibitors; mass spectrometry; viral proteome; eIF2S2; TFAP2A
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MDPI and ACS Style

Bakovic, A.; Bhalla, N.; Alem, F.; Campbell, C.; Zhou, W.; Narayanan, A. Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3. Viruses 2021, 13, 1533. https://doi.org/10.3390/v13081533

AMA Style

Bakovic A, Bhalla N, Alem F, Campbell C, Zhou W, Narayanan A. Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3. Viruses. 2021; 13(8):1533. https://doi.org/10.3390/v13081533

Chicago/Turabian Style

Bakovic, Allison, Nishank Bhalla, Farhang Alem, Catherine Campbell, Weidong Zhou, and Aarthi Narayanan. 2021. "Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3" Viruses 13, no. 8: 1533. https://doi.org/10.3390/v13081533

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