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.
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.
Nat Struct Mol Biol. 2014 Dec;21(12):1058-67. doi: 10.1038/nsmb.2922. Epub 2014 Nov 24.
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.
烃 stapling 可以将天然肽的生物活性 α-螺旋结构恢复，从而产生研究工具和原型治疗药物来剖析和靶向蛋白质相互作用。在这里，我们探索了肽 stapling 生成高保真、抗蛋白酶的抗原结构模拟物以用于疫苗开发的能力。迄今为止，HIV-1 一直对疫苗技术有抵抗力，尽管某些人类抗体可以通过靶向 gp41 跨膜融合装置的序列来广泛中和 HIV-1。为了开发候选 HIV-1 免疫原，我们生成并表征了 gp41 的膜近端外部区域（SAH-MPER）的稳定 α-螺旋。SAH-MPER 肽具有惊人的抗蛋白酶性，并且与广泛中和的 4E10 和 10E8 抗体高亲和力结合，当由两种抗 HIV Fabs 不同地参与时，重现了 MPER 表位的结构。因此， stapled 肽可能为疫苗接种提供了开发化学稳定抗原的新机会。
Zotero 插件
