Potent peptidic fusion inhibitors of influenza virus

doi:https://doi.org/10.1126/science.aan0516

Title: Potent peptidic fusion inhibitors of influenza virus

Abstract

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.

Authors:

;

; Vogels, Ronald; Friesen, Robert H. E.; Goudsmit, Jaap;

;

Publication Date:: 2017-09-28

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: National Institutes of Health (NIH)

OSTI Identifier:: 1408128

Resource Type:: Journal Article

Journal Name:: Science

Additional Journal Information:: Journal Volume: 358; Journal Issue: 6362; Journal ID: ISSN 0036-8075

Publisher:: AAAS

Country of Publication:: United States

Language:: ENGLISH

Subject:: 60 APPLIED LIFE SCIENCES

Citation Formats


                    Kadam, Rameshwar U., Juraszek, Jarek, Brandenburg, Boerries, Buyck, Christophe, Schepens, Wim B.  G., Kesteleyn, Bart, Stoops, Bart, Vreeken, Rob J., Vermond, Jan, Goutier, Wouter, Tang, Chan, Vogels, Ronald, Friesen, Robert H.  E., Goudsmit, Jaap, van Dongen, Maria J.  P., and Wilson, Ian A. Potent peptidic fusion inhibitors of influenza virus.  United States: N. p., 2017. 
        Web.  doi:10.1126/science.aan0516.

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                    Kadam, Rameshwar U., Juraszek, Jarek, Brandenburg, Boerries, Buyck, Christophe, Schepens, Wim B.  G., Kesteleyn, Bart, Stoops, Bart, Vreeken, Rob J., Vermond, Jan, Goutier, Wouter, Tang, Chan, Vogels, Ronald, Friesen, Robert H.  E., Goudsmit, Jaap, van Dongen, Maria J.  P., & Wilson, Ian A. Potent peptidic fusion inhibitors of influenza virus.  United States.  https://doi.org/10.1126/science.aan0516

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                    Kadam, Rameshwar U., Juraszek, Jarek, Brandenburg, Boerries, Buyck, Christophe, Schepens, Wim B.  G., Kesteleyn, Bart, Stoops, Bart, Vreeken, Rob J., Vermond, Jan, Goutier, Wouter, Tang, Chan, Vogels, Ronald, Friesen, Robert H.  E., Goudsmit, Jaap, van Dongen, Maria J.  P., and Wilson, Ian A. Thu .  
        "Potent peptidic fusion inhibitors of influenza virus".  United States.  https://doi.org/10.1126/science.aan0516.

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@article{osti_1408128,

  title        = {Potent peptidic fusion inhibitors of influenza virus},

  author       = {Kadam, Rameshwar U. and Juraszek, Jarek and Brandenburg, Boerries and Buyck, Christophe and Schepens, Wim B.  G. and Kesteleyn, Bart and Stoops, Bart and Vreeken, Rob J. and Vermond, Jan and Goutier, Wouter and Tang, Chan and Vogels, Ronald and Friesen, Robert H.  E. and Goudsmit, Jaap and van Dongen, Maria J.  P. and Wilson, Ian A.},

  abstractNote = {Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.},

  doi          = {10.1126/science.aan0516},

  url          = {https://www.osti.gov/biblio/1408128},
  journal      = {Science},

  issn         = {0036-8075},

  number       = 6362,

  volume       = 358,

  place        = {United States},

  year         = {2017},

  month        = {9}

}

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Similar Records

Title: Potent peptidic fusion inhibitors of influenza virus

Abstract

Citation Formats

Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif journal, October 1999

Structure of influenza haemagglutinin at the pH of membrane fusion journal, September 1994

A complementarity-determining region synthetic peptide acts as a miniantibody and neutralizes human immunodeficiency virus type 1 in vitro. journal, May 1993

H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes journal, August 2004

An In Vivo Human-Plasmablast Enrichment Technique Allows Rapid Identification of Therapeutic Influenza A Antibodies journal, July 2013

Protection from the 2009 H1N1 Pandemic Influenza by an Antibody from Combinatorial Survivor-Based Libraries journal, July 2010

A peptide mimetic of an anti-CD4 monoclonal antibody by rational design journal, July 2003

Structures of influenza A proteins and insights into antiviral drug targets journal, April 2010

MolProbity : all-atom structure validation for macromolecular crystallography journal, December 2009

Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing journal, May 2012

Coot model-building tools for molecular graphics journal, November 2004

Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin journal, June 2000

Dual Resistance to Adamantanes and Oseltamivir Among Seasonal Influenza A(H1N1) Viruses: 2008–2010 journal, January 2011

The Future of Peptide-based Drugs journal, December 2012

Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus journal, March 2004

Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution journal, January 1981

Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin journal, May 2011

PHENIX : building new software for automated crystallographic structure determination journal, October 2002

Mechanisms of Hemagglutinin Targeted Influenza Virus Neutralization journal, December 2013

Analytical molecular surface calculation journal, October 1983

A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins journal, July 2011

Global Transmission of Oseltamivir-Resistant Influenza journal, March 2009

Cross-neutralization of influenza A viruses mediated by a single antibody loop journal, September 2012

Antiviral agents active against influenza A viruses journal, December 2006

Antibody Recognition of a Highly Conserved Influenza Virus Epitope journal, April 2009

Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses journal, February 2009

Highly Conserved Protective Epitopes on Influenza B Viruses journal, August 2012

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol journal, December 2016

Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA journal, October 2012

Likelihood-enhanced fast translation functions journal, March 2005

Phaser crystallographic software journal, July 2007

Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif
journal, October 1999

Structure of influenza haemagglutinin at the pH of membrane fusion
journal, September 1994

A complementarity-determining region synthetic peptide acts as a miniantibody and neutralizes human immunodeficiency virus type 1 in vitro.
journal, May 1993

H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes
journal, August 2004

An In Vivo Human-Plasmablast Enrichment Technique Allows Rapid Identification of Therapeutic Influenza A Antibodies
journal, July 2013

Protection from the 2009 H1N1 Pandemic Influenza by an Antibody from Combinatorial Survivor-Based Libraries
journal, July 2010

A peptide mimetic of an anti-CD4 monoclonal antibody by rational design
journal, July 2003

Structures of influenza A proteins and insights into antiviral drug targets
journal, April 2010

MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing
journal, May 2012

Coot model-building tools for molecular graphics
journal, November 2004

Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin
journal, June 2000

Dual Resistance to Adamantanes and Oseltamivir Among Seasonal Influenza A(H1N1) Viruses: 2008–2010
journal, January 2011

The Future of Peptide-based Drugs
journal, December 2012

Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus
journal, March 2004

Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution
journal, January 1981

Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin
journal, May 2011

PHENIX : building new software for automated crystallographic structure determination
journal, October 2002

Mechanisms of Hemagglutinin Targeted Influenza Virus Neutralization
journal, December 2013

Analytical molecular surface calculation
journal, October 1983

A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins
journal, July 2011

Global Transmission of Oseltamivir-Resistant Influenza
journal, March 2009

Cross-neutralization of influenza A viruses mediated by a single antibody loop
journal, September 2012

Antiviral agents active against influenza A viruses
journal, December 2006

Antibody Recognition of a Highly Conserved Influenza Virus Epitope
journal, April 2009

Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses
journal, February 2009

Highly Conserved Protective Epitopes on Influenza B Viruses
journal, August 2012

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol
journal, December 2016

Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA
journal, October 2012

Likelihood-enhanced fast translation functions
journal, March 2005

Phaser crystallographic software
journal, July 2007