Identification of novel antivirals inhibiting recognition of Venezuelan equine encephalitis virus capsid protein by the Importin α/β1 heterodimer through high-throughput screening

David R. Thomas, Lindsay Lundberg, Chelsea Pinkham, Sharon Shechter, Aaron DeBono, Jonathan Baell, Kylie M. Wagstaff, Caroline A. Hick, Kylene Kehn-Hall, David A. Jans

Research output: Contribution to journalArticle

Abstract

Although the alphavirus Venezuelan equine encephalitis virus (VEEV) has been the cause of multiple outbreaks resulting in extensive human and equine mortality and morbidity, there are currently no anti-VEEV therapeutics available. VEEV pathogenicity is largely dependent on targeting of the viral capsid protein (CP) to the host cell nucleus through the nuclear transporting importin (Imp) α/β1 heterodimer. Here we perform a high-throughput screen, combined with nested counterscreens to identify small molecules able to inhibit the Impα/β1:CP interaction for the first time. Several compounds were able to significantly reduce viral replication in infected cells. Compound G281-1564 in particular could inhibit VEEV replication at low μM concentration, while showing minimal toxicity, with steady state and dynamic quantitative microscopic measurements confirming its ability to inhibit CP nuclear import. This study establishes the principle that inhibitors of CP nucleocytoplasmic trafficking can have potent antiviral activity against VEEV, and represents a platform for future development of safe anti-VEEV compounds with high efficacy and specificity.

LanguageEnglish
Pages8-19
Number of pages12
JournalAntiviral Research
Volume151
DOIs
StatePublished - 1 Mar 2018

Keywords

  • Antivirals
  • High-throughput screen
  • Importins
  • Quantitative microscopy
  • VEEV

Cite this

@article{aee6cf5daeb542a79d45c5b6c2b96b64,
title = "Identification of novel antivirals inhibiting recognition of Venezuelan equine encephalitis virus capsid protein by the Importin α/β1 heterodimer through high-throughput screening",
abstract = "Although the alphavirus Venezuelan equine encephalitis virus (VEEV) has been the cause of multiple outbreaks resulting in extensive human and equine mortality and morbidity, there are currently no anti-VEEV therapeutics available. VEEV pathogenicity is largely dependent on targeting of the viral capsid protein (CP) to the host cell nucleus through the nuclear transporting importin (Imp) α/β1 heterodimer. Here we perform a high-throughput screen, combined with nested counterscreens to identify small molecules able to inhibit the Impα/β1:CP interaction for the first time. Several compounds were able to significantly reduce viral replication in infected cells. Compound G281-1564 in particular could inhibit VEEV replication at low μM concentration, while showing minimal toxicity, with steady state and dynamic quantitative microscopic measurements confirming its ability to inhibit CP nuclear import. This study establishes the principle that inhibitors of CP nucleocytoplasmic trafficking can have potent antiviral activity against VEEV, and represents a platform for future development of safe anti-VEEV compounds with high efficacy and specificity.",
keywords = "Antivirals, High-throughput screen, Importins, Quantitative microscopy, VEEV",
author = "Thomas, {David R.} and Lindsay Lundberg and Chelsea Pinkham and Sharon Shechter and Aaron DeBono and Jonathan Baell and Wagstaff, {Kylie M.} and Hick, {Caroline A.} and Kylene Kehn-Hall and Jans, {David A.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1016/j.antiviral.2018.01.007",
language = "English",
volume = "151",
pages = "8--19",
journal = "Antiviral Research",
issn = "0166-3542",
publisher = "Elsevier",

}

TY - JOUR

T1 - Identification of novel antivirals inhibiting recognition of Venezuelan equine encephalitis virus capsid protein by the Importin α/β1 heterodimer through high-throughput screening

AU - Thomas,David R.

AU - Lundberg,Lindsay

AU - Pinkham,Chelsea

AU - Shechter,Sharon

AU - DeBono,Aaron

AU - Baell,Jonathan

AU - Wagstaff,Kylie M.

AU - Hick,Caroline A.

AU - Kehn-Hall,Kylene

AU - Jans,David A.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Although the alphavirus Venezuelan equine encephalitis virus (VEEV) has been the cause of multiple outbreaks resulting in extensive human and equine mortality and morbidity, there are currently no anti-VEEV therapeutics available. VEEV pathogenicity is largely dependent on targeting of the viral capsid protein (CP) to the host cell nucleus through the nuclear transporting importin (Imp) α/β1 heterodimer. Here we perform a high-throughput screen, combined with nested counterscreens to identify small molecules able to inhibit the Impα/β1:CP interaction for the first time. Several compounds were able to significantly reduce viral replication in infected cells. Compound G281-1564 in particular could inhibit VEEV replication at low μM concentration, while showing minimal toxicity, with steady state and dynamic quantitative microscopic measurements confirming its ability to inhibit CP nuclear import. This study establishes the principle that inhibitors of CP nucleocytoplasmic trafficking can have potent antiviral activity against VEEV, and represents a platform for future development of safe anti-VEEV compounds with high efficacy and specificity.

AB - Although the alphavirus Venezuelan equine encephalitis virus (VEEV) has been the cause of multiple outbreaks resulting in extensive human and equine mortality and morbidity, there are currently no anti-VEEV therapeutics available. VEEV pathogenicity is largely dependent on targeting of the viral capsid protein (CP) to the host cell nucleus through the nuclear transporting importin (Imp) α/β1 heterodimer. Here we perform a high-throughput screen, combined with nested counterscreens to identify small molecules able to inhibit the Impα/β1:CP interaction for the first time. Several compounds were able to significantly reduce viral replication in infected cells. Compound G281-1564 in particular could inhibit VEEV replication at low μM concentration, while showing minimal toxicity, with steady state and dynamic quantitative microscopic measurements confirming its ability to inhibit CP nuclear import. This study establishes the principle that inhibitors of CP nucleocytoplasmic trafficking can have potent antiviral activity against VEEV, and represents a platform for future development of safe anti-VEEV compounds with high efficacy and specificity.

KW - Antivirals

KW - High-throughput screen

KW - Importins

KW - Quantitative microscopy

KW - VEEV

UR - http://www.scopus.com/inward/record.url?scp=85040648356&partnerID=8YFLogxK

U2 - 10.1016/j.antiviral.2018.01.007

DO - 10.1016/j.antiviral.2018.01.007

M3 - Article

VL - 151

SP - 8

EP - 19

JO - Antiviral Research

T2 - Antiviral Research

JF - Antiviral Research

SN - 0166-3542

ER -