Cysteine Cathepsin Inhibitors as Anti-Ebola Agents

Wouter A. Van Der Linden; Christopher J. Schulze; Andrew S. Herbert; Tyler B. Krause; Ariel A. Wirchnianski; John M. Dye; Kartik Chandran; Matthew Bogyo

doi:10.1021/acsinfecdis.5b00130

Cysteine Cathepsin Inhibitors as Anti-Ebola Agents

Wouter A. Van Der Linden, Christopher J. Schulze, Andrew S. Herbert, Tyler B. Krause, Ariel A. Wirchnianski, John M. Dye, Kartik Chandran, Matthew Bogyo

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

The recent Ebola virus outbreak in western Africa highlights the need for novel therapeutics that target Ebola virus and other filoviruses. Filoviruses require processing by host cell-derived cysteine cathepsins for productive infection. Here we report the generation of a focused library of cysteine cathepsin inhibitors and subsequent screening to identify compounds with potent activity against viral entry and replication. Our top compounds show highly potent and broad-spectrum activity against cysteine cathepsins and were able to effectively block entry of Ebola and Marburg viruses. These agents are promising leads for development as antifilovirus therapeutics.

Original language	English (US)
Pages (from-to)	173-179
Number of pages	7
Journal	ACS Infectious Diseases
Volume	2
Issue number	3
DOIs	https://doi.org/10.1021/acsinfecdis.5b00130
State	Published - Mar 11 2016

Keywords

Ebola virus
cathepsin inhibitor
filovirus
inhibition of host cell entry

ASJC Scopus subject areas

Infectious Diseases

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10.1021/acsinfecdis.5b00130

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title = "Cysteine Cathepsin Inhibitors as Anti-Ebola Agents",

abstract = "The recent Ebola virus outbreak in western Africa highlights the need for novel therapeutics that target Ebola virus and other filoviruses. Filoviruses require processing by host cell-derived cysteine cathepsins for productive infection. Here we report the generation of a focused library of cysteine cathepsin inhibitors and subsequent screening to identify compounds with potent activity against viral entry and replication. Our top compounds show highly potent and broad-spectrum activity against cysteine cathepsins and were able to effectively block entry of Ebola and Marburg viruses. These agents are promising leads for development as antifilovirus therapeutics.",

keywords = "Ebola virus, cathepsin inhibitor, filovirus, inhibition of host cell entry",

author = "{Van Der Linden}, {Wouter A.} and Schulze, {Christopher J.} and Herbert, {Andrew S.} and Krause, {Tyler B.} and Wirchnianski, {Ariel A.} and Dye, {John M.} and Kartik Chandran and Matthew Bogyo",

note = "Funding Information: We thank S. R. Lynch at the Stanford University Department of Chemistry NMR facility for assistance. This work was supported by National Institutes of Health Grants R01 EB005011 (to M.B.) and R01 AI088027 (to K.C.) and the Defense Threat Reduction Agency funding CB3873 (J.M.D.). W.A.v.d.L. was supported by a Rubicon fellowship from The Netherlands Organization for Scientific Research (NWO). Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

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doi = "10.1021/acsinfecdis.5b00130",

language = "English (US)",

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AU - Van Der Linden, Wouter A.

AU - Schulze, Christopher J.

AU - Herbert, Andrew S.

AU - Krause, Tyler B.

AU - Wirchnianski, Ariel A.

AU - Dye, John M.

AU - Chandran, Kartik

AU - Bogyo, Matthew

N1 - Funding Information: We thank S. R. Lynch at the Stanford University Department of Chemistry NMR facility for assistance. This work was supported by National Institutes of Health Grants R01 EB005011 (to M.B.) and R01 AI088027 (to K.C.) and the Defense Threat Reduction Agency funding CB3873 (J.M.D.). W.A.v.d.L. was supported by a Rubicon fellowship from The Netherlands Organization for Scientific Research (NWO). Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/3/11

Y1 - 2016/3/11

N2 - The recent Ebola virus outbreak in western Africa highlights the need for novel therapeutics that target Ebola virus and other filoviruses. Filoviruses require processing by host cell-derived cysteine cathepsins for productive infection. Here we report the generation of a focused library of cysteine cathepsin inhibitors and subsequent screening to identify compounds with potent activity against viral entry and replication. Our top compounds show highly potent and broad-spectrum activity against cysteine cathepsins and were able to effectively block entry of Ebola and Marburg viruses. These agents are promising leads for development as antifilovirus therapeutics.

AB - The recent Ebola virus outbreak in western Africa highlights the need for novel therapeutics that target Ebola virus and other filoviruses. Filoviruses require processing by host cell-derived cysteine cathepsins for productive infection. Here we report the generation of a focused library of cysteine cathepsin inhibitors and subsequent screening to identify compounds with potent activity against viral entry and replication. Our top compounds show highly potent and broad-spectrum activity against cysteine cathepsins and were able to effectively block entry of Ebola and Marburg viruses. These agents are promising leads for development as antifilovirus therapeutics.

KW - Ebola virus

KW - cathepsin inhibitor

KW - filovirus

KW - inhibition of host cell entry

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Cysteine Cathepsin Inhibitors as Anti-Ebola Agents

Abstract

Keywords

ASJC Scopus subject areas

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