Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design

Sharon Shechter, David R. Thomas, Lindsay Lundberg, Chelsea Pinkham, Shih Chao Lin, Kylie M. Wagstaff, Aaron Debono, Kylene Kehn-Hall, David A. Jans

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Therapeutics are currently unavailable for Venezuelan equine encephalitis virus (VEEV), which elicits flu-like symptoms and encephalitis in humans, with an estimated 14% of cases resulting in neurological disease. Here we identify anti-VEEV agents using in silico structure-based-drug-design (SBDD) for the first time, characterising inhibitors that block recognition of VEEV capsid protein (C) by the host importin (IMP) α/β1 nuclear transport proteins. From an initial screen of 1.5 million compounds, followed by in silico refinement and screening for biological activity in vitro, we identified 21 hit compounds which inhibited IMPα/β1:C binding with IC50s as low as 5 μM. Four compounds were found to inhibit nuclear import of C in transfected cells, with one able to reduce VEEV replication at μM concentration, concomitant with reduced C nuclear accumulation in infected cells. Further, this compound was inactive against a mutant VEEV that lacks high affinity IMPα/β1:C interaction, supporting the mode of its antiviral action to be through inhibiting C nuclear localization. This successful application of SBDD paves the way for lead optimization for VEEV antivirals, and is an exciting prospect to identify inhibitors for the many other viral pathogens of significance that require IMPα/β1 in their infectious cycle.

Original languageEnglish
Article number17705
Number of pages16
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

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title = "Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design",
abstract = "Therapeutics are currently unavailable for Venezuelan equine encephalitis virus (VEEV), which elicits flu-like symptoms and encephalitis in humans, with an estimated 14{\%} of cases resulting in neurological disease. Here we identify anti-VEEV agents using in silico structure-based-drug-design (SBDD) for the first time, characterising inhibitors that block recognition of VEEV capsid protein (C) by the host importin (IMP) α/β1 nuclear transport proteins. From an initial screen of 1.5 million compounds, followed by in silico refinement and screening for biological activity in vitro, we identified 21 hit compounds which inhibited IMPα/β1:C binding with IC50s as low as 5 μM. Four compounds were found to inhibit nuclear import of C in transfected cells, with one able to reduce VEEV replication at μM concentration, concomitant with reduced C nuclear accumulation in infected cells. Further, this compound was inactive against a mutant VEEV that lacks high affinity IMPα/β1:C interaction, supporting the mode of its antiviral action to be through inhibiting C nuclear localization. This successful application of SBDD paves the way for lead optimization for VEEV antivirals, and is an exciting prospect to identify inhibitors for the many other viral pathogens of significance that require IMPα/β1 in their infectious cycle.",
author = "Sharon Shechter and Thomas, {David R.} and Lindsay Lundberg and Chelsea Pinkham and Lin, {Shih Chao} and Wagstaff, {Kylie M.} and Aaron Debono and Kylene Kehn-Hall and Jans, {David A.}",
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Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design. / Shechter, Sharon; Thomas, David R.; Lundberg, Lindsay; Pinkham, Chelsea; Lin, Shih Chao; Wagstaff, Kylie M.; Debono, Aaron; Kehn-Hall, Kylene; Jans, David A.

In: Scientific Reports, Vol. 7, No. 1, 17705, 01.12.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Shechter, Sharon

AU - Thomas, David R.

AU - Lundberg, Lindsay

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AU - Wagstaff, Kylie M.

AU - Debono, Aaron

AU - Kehn-Hall, Kylene

AU - Jans, David A.

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