Potent peptidic fusion inhibitors of influenza virus

doi:10.1126/science.aan0516

Title: Potent peptidic fusion inhibitors of influenza virus

Full Record
Other Related Research

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.

Copy to clipboard


                    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.  doi:10.1126/science.aan0516.

Copy to clipboard


                    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.  doi:10.1126/science.aan0516.

Copy to clipboard


                    
@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},

  journal      = {Science},

  issn         = {0036-8075},

  number       = 6362,

  volume       = 358,

  place        = {United States},

  year         = {2017},

  month        = {9}

}

Copy to clipboard

Journal Article:

DOI: 10.1126/science.aan0516

Other availability

Find in Google Scholar

Search WorldCat to find libraries that may hold this journal

Save / Share:

Export Metadata

Save to My Library

Similar records in OSTI.GOV collections:

Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge

Journal Article Nachbagauer, Raffael ; Shore, David ; Yang, Hua ; ... - Journal of Virology

ABSTRACT Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity,in vitroneutralization capacity, andin vivoprotective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1more »« less
DOI: 10.1128/JVI.00949-18
Antibody Recognition of a Highly Conserved Influenza Virus Epitope

Journal Article Ekiert, Damian C. ; Bhabha, Gira ; Elsliger, Marc-André ; ... - Science

Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes amore »« less
DOI: 10.1126/science.1171491
A human monoclonal antibody derived from a vaccinated volunteer recognizes heterosubtypically a novel epitope on the hemagglutinin globular head of H1 and H9 influenza A viruses

Journal Article Boonsathorn, Naphatsawan ; Panthong, Sumolrat ; Japan Science and Technology Agency/Japan International Cooperation Agency, Science and Technology Research Partnership for Sustainable Development ; ... - Biochemical and Biophysical Research Communications

Highlights: • A human monoclonal antibody against influenza virus was produced from a volunteer. • The antibody was generated from the PBMCs of the volunteer using the fusion method. • The antibody neutralized heterosubtypically group 1 influenza A viruses (H1 and H9). • The antibody targeted a novel epitope in globular head region of the hemagglutinin. • Sequences of the identified epitope are highly conserved among H1 and H9 subtypes. - Abstract: Most neutralizing antibodies elicited during influenza virus infection or by vaccination have a narrow spectrum because they usually target variable epitopes in the globular head region of hemagglutininmore »« less
DOI: 10.1016/J.BBRC.2014.09.008
Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient

Journal Article Hu, Weibin ; Chen, Aizhong ; Miao, Yi ; ... - Virology

Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross-protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarilymore »« less
DOI: 10.1016/J.VIROL.2012.09.034
Human monoclonal antibodies derived from a patient infected with 2009 pandemic influenza A virus broadly cross-neutralize group 1 influenza viruses

Journal Article Pan, Yang ; Sasaki, Tadahiro ; JST/JICA, Science and Technology Research Partnership for Sustainable Development ; ... - Biochemical and Biophysical Research Communications

Highlights: • Influenza infection can elicit heterosubtypic antibodies to group 1 influenza virus. • Three human monoclonal antibodies were generated from an H1N1-infected patient. • The antibodies predominantly recognized α-helical stem of viral hemagglutinin (HA). • The antibodies inhibited HA structural activation during the fusion process. • The antibodies are potential candidates for future antibody therapy to influenza. - Abstract: Influenza viruses are a continuous threat to human public health because of their ability to evolve rapidly through genetic drift and reassortment. Three human monoclonal antibodies (HuMAbs) were generated in this study, 1H11, 2H5 and 5G2, and they cross-neutralize amore »« less
DOI: 10.1016/J.BBRC.2014.05.060

Similar Records