title: Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies.
abstract: Hydrocarbon stapling can restore bioactive α-helical structure to natural peptides, yielding research tools and prototype therapeutics to dissect and target protein interactions. Here we explore the capacity of peptide stapling to generate high-fidelity, protease-resistant mimics of antigenic structures for vaccine development. HIV-1 has been refractory to vaccine technologies thus far, although select human antibodies can broadly neutralize HIV-1 by targeting sequences of the gp41 juxtamembrane fusion apparatus. To develop candidate HIV-1 immunogens, we generated and characterized stabilized α-helices of the membrane-proximal external region (SAH-MPER) of gp41. SAH-MPER peptides were remarkably protease resistant and bound to the broadly neutralizing 4E10 and 10E8 antibodies with high affinity, recapitulating the structure of the MPER epitope when differentially engaged by the two anti-HIV Fabs. Thus, stapled peptides may provide a new opportunity to develop chemically stabilized antigens for vaccination.
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Bird
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California, USA. [2] International AIDS Vaccine Initiative Neutralizing Antibody Center, Scripps Research Institute, La Jolla, California, USA. [3] Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, California, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Irimia
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gilad
authors.initials: G
authors.lastname: Ofek
authors.affiliation: Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California, USA. [2] International AIDS Vaccine Initiative Neutralizing Antibody Center, Scripps Research Institute, La Jolla, California, USA. [3] Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D000080908:Broadly Neutralizing Antibodies; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*
chemical_list: C558559:4E10 monoclonal antibody; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D010455:Peptides