Bird, GregoryIrimia, AdrianaOfek, GiladKwong, Peter D.Wilson, Ian A.Walensky, Loren2015-07-132014Bird, Gregory H., Adriana Irimia, Gilad Ofek, Peter D. Kwong, Ian A. Wilson, and Loren D. Walensky. 2014. “Stapled HIV-1 Peptides Recapitulate Antigenic Structures and Engage Broadly Neutralizing Antibodies.” Nature structural & molecular biology 21 (12): 1058-1067. doi:10.1038/nsmb.2922. http://dx.doi.org/10.1038/nsmb.2922.1545-9993http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295722Hydrocarbon 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.en-USJournal Article2015-07-1310.1038/nsmb.2922