Identification of novel cellular targets for therapeutic intervention against ebola virus infection by siRNA screening

Andrey A. Kolokoltsov, Mohammad F. Saeed, Alexander Freiberg, Michael R. Holbrook, Robert A. Davey

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

While much progress has been made in developing drugs against a few prominent viruses such as HIV, few examples exist for emerging infectious agents. In some cases, broad spectrum anti-viral drugs, such as ribavirin, are effective, but for some groups of viruses, these show little efficacy in animal models. Traditional methods focus on screening small molecule libraries to identify drugs that target virus factors, with the intention that side-effects to the host can be minimized. However, this greatly limits potential drug targets and virus genes can rapidly mutate to avoid drug action. Recent advances in siRNA gene-targeting technologies have provided a powerful tool to specifically target and suppress the expression of cell genes. Since viruses are completely dependent upon host cell proteins for propagation, siRNA screening promises to reveal novel cell proteins and signaling pathways that may be viable targets for drug therapy regimens. Here we used an siRNA screening approach to identify gene products that play critical roles in Ebola virus infection. By gene cluster analysis, proteins in phosphatidylinositol-3-kinase and calcium/calmodulin kinase related networks were identified as important for Zaire Ebola virus infection and prioritized for further evaluation. The key roles of each were confirmed by testing available drugs specific for members of each pathway. Interestingly, both sets of proteins are also important in cancer and subject to intense investigation. Thus, development of new drugs against these cancer targets may also prove useful in combating Ebola virus.

Original languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalDrug Development Research
Volume70
Issue number4
DOIs
StatePublished - Jun 2009

Fingerprint

Ebola Hemorrhagic Fever
Small Interfering RNA
Viruses
Pharmaceutical Preparations
Ebolavirus
Therapeutics
Proteins
Phosphatidylinositol 3-Kinase
Small Molecule Libraries
Calcium-Calmodulin-Dependent Protein Kinases
Gene Targeting
Ribavirin
Multigene Family
Genes
Cluster Analysis
Neoplasms
Animal Models
HIV
Calcium
Technology

Keywords

  • Antiviral
  • CAMK2
  • Ebola virus
  • PI3 kinase

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Identification of novel cellular targets for therapeutic intervention against ebola virus infection by siRNA screening. / Kolokoltsov, Andrey A.; Saeed, Mohammad F.; Freiberg, Alexander; Holbrook, Michael R.; Davey, Robert A.

In: Drug Development Research, Vol. 70, No. 4, 06.2009, p. 255-265.

Research output: Contribution to journalArticle

Kolokoltsov, Andrey A. ; Saeed, Mohammad F. ; Freiberg, Alexander ; Holbrook, Michael R. ; Davey, Robert A. / Identification of novel cellular targets for therapeutic intervention against ebola virus infection by siRNA screening. In: Drug Development Research. 2009 ; Vol. 70, No. 4. pp. 255-265.
@article{6ca07b7bb572491cb997a9313e184237,
title = "Identification of novel cellular targets for therapeutic intervention against ebola virus infection by siRNA screening",
abstract = "While much progress has been made in developing drugs against a few prominent viruses such as HIV, few examples exist for emerging infectious agents. In some cases, broad spectrum anti-viral drugs, such as ribavirin, are effective, but for some groups of viruses, these show little efficacy in animal models. Traditional methods focus on screening small molecule libraries to identify drugs that target virus factors, with the intention that side-effects to the host can be minimized. However, this greatly limits potential drug targets and virus genes can rapidly mutate to avoid drug action. Recent advances in siRNA gene-targeting technologies have provided a powerful tool to specifically target and suppress the expression of cell genes. Since viruses are completely dependent upon host cell proteins for propagation, siRNA screening promises to reveal novel cell proteins and signaling pathways that may be viable targets for drug therapy regimens. Here we used an siRNA screening approach to identify gene products that play critical roles in Ebola virus infection. By gene cluster analysis, proteins in phosphatidylinositol-3-kinase and calcium/calmodulin kinase related networks were identified as important for Zaire Ebola virus infection and prioritized for further evaluation. The key roles of each were confirmed by testing available drugs specific for members of each pathway. Interestingly, both sets of proteins are also important in cancer and subject to intense investigation. Thus, development of new drugs against these cancer targets may also prove useful in combating Ebola virus.",
keywords = "Antiviral, CAMK2, Ebola virus, PI3 kinase",
author = "Kolokoltsov, {Andrey A.} and Saeed, {Mohammad F.} and Alexander Freiberg and Holbrook, {Michael R.} and Davey, {Robert A.}",
year = "2009",
month = "6",
doi = "10.1002/ddr.20303",
language = "English (US)",
volume = "70",
pages = "255--265",
journal = "Drug Development Research",
issn = "0272-4391",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Identification of novel cellular targets for therapeutic intervention against ebola virus infection by siRNA screening

AU - Kolokoltsov, Andrey A.

AU - Saeed, Mohammad F.

AU - Freiberg, Alexander

AU - Holbrook, Michael R.

AU - Davey, Robert A.

PY - 2009/6

Y1 - 2009/6

N2 - While much progress has been made in developing drugs against a few prominent viruses such as HIV, few examples exist for emerging infectious agents. In some cases, broad spectrum anti-viral drugs, such as ribavirin, are effective, but for some groups of viruses, these show little efficacy in animal models. Traditional methods focus on screening small molecule libraries to identify drugs that target virus factors, with the intention that side-effects to the host can be minimized. However, this greatly limits potential drug targets and virus genes can rapidly mutate to avoid drug action. Recent advances in siRNA gene-targeting technologies have provided a powerful tool to specifically target and suppress the expression of cell genes. Since viruses are completely dependent upon host cell proteins for propagation, siRNA screening promises to reveal novel cell proteins and signaling pathways that may be viable targets for drug therapy regimens. Here we used an siRNA screening approach to identify gene products that play critical roles in Ebola virus infection. By gene cluster analysis, proteins in phosphatidylinositol-3-kinase and calcium/calmodulin kinase related networks were identified as important for Zaire Ebola virus infection and prioritized for further evaluation. The key roles of each were confirmed by testing available drugs specific for members of each pathway. Interestingly, both sets of proteins are also important in cancer and subject to intense investigation. Thus, development of new drugs against these cancer targets may also prove useful in combating Ebola virus.

AB - While much progress has been made in developing drugs against a few prominent viruses such as HIV, few examples exist for emerging infectious agents. In some cases, broad spectrum anti-viral drugs, such as ribavirin, are effective, but for some groups of viruses, these show little efficacy in animal models. Traditional methods focus on screening small molecule libraries to identify drugs that target virus factors, with the intention that side-effects to the host can be minimized. However, this greatly limits potential drug targets and virus genes can rapidly mutate to avoid drug action. Recent advances in siRNA gene-targeting technologies have provided a powerful tool to specifically target and suppress the expression of cell genes. Since viruses are completely dependent upon host cell proteins for propagation, siRNA screening promises to reveal novel cell proteins and signaling pathways that may be viable targets for drug therapy regimens. Here we used an siRNA screening approach to identify gene products that play critical roles in Ebola virus infection. By gene cluster analysis, proteins in phosphatidylinositol-3-kinase and calcium/calmodulin kinase related networks were identified as important for Zaire Ebola virus infection and prioritized for further evaluation. The key roles of each were confirmed by testing available drugs specific for members of each pathway. Interestingly, both sets of proteins are also important in cancer and subject to intense investigation. Thus, development of new drugs against these cancer targets may also prove useful in combating Ebola virus.

KW - Antiviral

KW - CAMK2

KW - Ebola virus

KW - PI3 kinase

UR - http://www.scopus.com/inward/record.url?scp=67649356905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649356905&partnerID=8YFLogxK

U2 - 10.1002/ddr.20303

DO - 10.1002/ddr.20303

M3 - Article

AN - SCOPUS:67649356905

VL - 70

SP - 255

EP - 265

JO - Drug Development Research

JF - Drug Development Research

SN - 0272-4391

IS - 4

ER -