Repurposed FDA-Approved drug sorafenib reduces replication of Venezuelan equine encephalitis virus and other alphaviruses.

Authors:
Lindsay Lundberg
Lindsay Lundberg
George Mason University
United States
Ashwini Brahms
Ashwini Brahms
George Mason University
Idris Hooper
Idris Hooper
National Center for Biodefense and Infectious Diseases
Brian Carey
Brian Carey
Bantry General Hospital
Bibha Dahal
Bibha Dahal
South Dakota State University
Brookings | United States
Aarthi Narayanan
Aarthi Narayanan
National Center for Biodefense and Infectious Diseases
United States
Kylene Kehn-Hall
Kylene Kehn-Hall
United States

Antiviral Res 2018 09 5;157:57-67. Epub 2018 Jul 5.

National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA. Electronic address:

The New World alphaviruses -Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, and WEEV respectively) - cause a febrile disease that is often lethal in equines and children and leads to long-term neurological sequelae in survivors. Endemic to the Americas, epizootic outbreaks of the three viruses occur sporadically in the continental United States. All three viruses aerosolize readily, replicate to high titers in cell culture, and have low infectious doses. Additionally, there are no FDA-approved vaccines or therapeutics for human use. To address the therapeutic gap, a high throughput assay utilizing a luciferase reporter virus, TC83-luc, was performed to screen a library of commercially available, FDA-approved drugs for antiviral activity. From a group of twenty compounds found to significantly decrease luminescence, the carcinoma therapeutic sorafenib inhibited replication of VEEV-TC83 and TrD in vitro. Additionally, sorafenib inhibited replication of EEEV and two Old World alphaviruses, Sindbis virus and chikungunya virus, at 8 and 16 h post-infection. Sorafenib caused no toxicity in Vero cells, and coupled with a low EC value, yielded a selectivity index of >19. Mechanism of actions studies suggest that sorafenib inhibited viral translation through dephosphorylation of several key proteins, including eIF4E and p70S6K, leading to a reduction in viral protein production and overall viral replication.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S01663542183006
Publisher Site
http://dx.doi.org/10.1016/j.antiviral.2018.07.005DOI Listing
September 2018
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