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:
- Publication Date:
- 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.
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
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.
@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}
}
Works referenced in this record:
Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif
journal, October 1999
- Ton-That, H.; Liu, G.; Mazmanian, S. K.
- Proceedings of the National Academy of Sciences, Vol. 96, Issue 22
Structure of influenza haemagglutinin at the pH of membrane fusion
journal, September 1994
- Bullough, Per A.; Hughson, Frederick M.; Skehel, John J.
- Nature, Vol. 371, Issue 6492
A complementarity-determining region synthetic peptide acts as a miniantibody and neutralizes human immunodeficiency virus type 1 in vitro.
journal, May 1993
- Levi, M.; Sallberg, M.; Ruden, U.
- Proceedings of the National Academy of Sciences, Vol. 90, Issue 10
H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes
journal, August 2004
- Russell, R. J.; Gamblin, S. J.; Haire, L. F.
- Virology, Vol. 325, Issue 2
An In Vivo Human-Plasmablast Enrichment Technique Allows Rapid Identification of Therapeutic Influenza A Antibodies
journal, July 2013
- Nakamura, Gerald; Chai, Ning; Park, Summer
- Cell Host & Microbe, Vol. 14, Issue 1
Protection from the 2009 H1N1 Pandemic Influenza by an Antibody from Combinatorial Survivor-Based Libraries
journal, July 2010
- Kashyap, Arun K.; Steel, John; Rubrum, Adam
- PLoS Pathogens, Vol. 6, Issue 7
A peptide mimetic of an anti-CD4 monoclonal antibody by rational design
journal, July 2003
- Casset, Florence; Roux, Florence; Mouchet, Patrick
- Biochemical and Biophysical Research Communications, Vol. 307, Issue 1
Structures of influenza A proteins and insights into antiviral drug targets
journal, April 2010
- Das, Kalyan; Aramini, James M.; Ma, Li-Chung
- Nature Structural & Molecular Biology, Vol. 17, Issue 5
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing
journal, May 2012
- Whitehead, Timothy A.; Chevalier, Aaron; Song, Yifan
- Nature Biotechnology, Vol. 30, Issue 6
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin
journal, June 2000
- Skehel, John J.; Wiley, Don C.
- Annual Review of Biochemistry, Vol. 69, Issue 1
Dual Resistance to Adamantanes and Oseltamivir Among Seasonal Influenza A(H1N1) Viruses: 2008–2010
journal, January 2011
- Sheu, Tiffany G.; Fry, Alicia M.; Garten, Rebecca J.
- The Journal of Infectious Diseases, Vol. 203, Issue 1
The Future of Peptide-based Drugs
journal, December 2012
- Craik, David J.; Fairlie, David P.; Liras, Spiros
- Chemical Biology & Drug Design, Vol. 81, Issue 1
Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus
journal, March 2004
- Stevens, J.
- Science, Vol. 303, Issue 5665
Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution
journal, January 1981
- Wilson, I. A.; Skehel, J. J.; Wiley, D. C.
- Nature, Vol. 289, Issue 5796
Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin
journal, May 2011
- Fleishman, S. J.; Whitehead, T. A.; Ekiert, D. C.
- Science, Vol. 332, Issue 6031
PHENIX : building new software for automated crystallographic structure determination
journal, October 2002
- Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
- Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
Mechanisms of Hemagglutinin Targeted Influenza Virus Neutralization
journal, December 2013
- Brandenburg, Boerries; Koudstaal, Wouter; Goudsmit, Jaap
- PLoS ONE, Vol. 8, Issue 12
Analytical molecular surface calculation
journal, October 1983
- Connolly, M. L.
- Journal of Applied Crystallography, Vol. 16, Issue 5
A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins
journal, July 2011
- Corti, D.; Voss, J.; Gamblin, S. J.
- Science, Vol. 333, Issue 6044
Global Transmission of Oseltamivir-Resistant Influenza
journal, March 2009
- Moscona, Anne
- New England Journal of Medicine, Vol. 360, Issue 10
Cross-neutralization of influenza A viruses mediated by a single antibody loop
journal, September 2012
- Ekiert, Damian C.; Kashyap, Arun K.; Steel, John
- Nature, Vol. 489, Issue 7417
Antiviral agents active against influenza A viruses
journal, December 2006
- De Clercq, Erik
- Nature Reviews Drug Discovery, Vol. 5, Issue 12
Antibody Recognition of a Highly Conserved Influenza Virus Epitope
journal, April 2009
- Ekiert, D. C.; Bhabha, G.; Elsliger, M. -A.
- Science, Vol. 324, Issue 5924
Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses
journal, February 2009
- Sui, Jianhua; Hwang, William C.; Perez, Sandra
- Nature Structural & Molecular Biology, Vol. 16, Issue 3
Highly Conserved Protective Epitopes on Influenza B Viruses
journal, August 2012
- Dreyfus, C.; Laursen, N. S.; Kwaks, T.
- Science, Vol. 337, Issue 6100
Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol
journal, December 2016
- Kadam, Rameshwar U.; Wilson, Ian A.
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 2
Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA
journal, October 2012
- Julien, Jean-Philippe; Lee, Peter S.; Wilson, Ian A.
- Immunological Reviews, Vol. 250, Issue 1
Likelihood-enhanced fast translation functions
journal, March 2005
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Storoni, Laurent C.
- Acta Crystallographica Section D Biological Crystallography, Vol. 61, Issue 4
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4