Stapled Antigens for HIV-1 Vaccination

用于 HIV-1 疫苗接种的钉合抗原

• 批准号: 7737500
• 负责人: Loren David Walensky
• 金额: $ 43.21万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737500
• 关键词: AIDS/HIV problem; Adopted; Amino Acid Sequence; Antibodies; Antibody Formation; Antigens; Binding; Chemicals; Chemistry; Chimeric Proteins; Development; Education; Epidemic; Epitopes; Face; Failure; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp41; HIV-1; HIV-1 vaccine; Heel; Human; Hydrocarbons; Immune system; Immunology; Infection; Masks; Membrane; Modeling; Molecular Conformation; Peptide Hydrolases; Peptides; Pharmacology; Preventive; Process; Resistance; Shapes; Structure; Technology; Testing; Vaccination; Vaccines; Viral; Virion; Virulent; glycosylation; immunogenicity; in vitro activity; in vivo; insight; multidisciplinary; neutralizing antibody; novel; pandemic disease; polypeptide; reconstitution; structural biology

DESCRIPTION (provided by applicant): HIV/AIDS is the world's foremost human epidemic. Historically, preventive vaccines that elicit neutralizing antibodies have achieved the greatest impact in curtailing epidemics. HIV-1 has thwarted modern vaccine technology by both eluding and destroying the host immune system. Critical viral epitopes are masked by glycosylation, exposed only fleetingly, or mutagenized beyond recognition. However, amidst this human immune system failure there have emerged rare but effective antibodies that broadly neutralize HIV-1 by targeting its juxtamembrane fusion apparatus. Thus, despite the historical failure to generate immunogens that elicit clinically effective anti-HIV-1 antibodies, we know from those relatively rare humans who naturally produce them that this goal is mechanistically and immunologically achievable. Several naturally-occurring anti-HIV antibodies specifically recognize structured amino acid sequences of gp41, a dynamic fusion protein that adopts a continuum of conformational changes during the process of HIV-1 infection. Fueled by fresh insights from the structural biology of these epitopes and their antibody interactions, the present challenge is to recreate the virulent face of HIV-1 and transform it into an Achilles' heel. This proposal aims to apply a novel chemical technology, termed hydrocarbon stapling, which both reinforces the bioactive structure of natural peptides and confers unprecedented protease resistance, to develop Stabilized Antigenic Structures of gp41 (SAS-gp41) for HIV-1 vaccination. Once synthesized, the stapled antigens, modeled after the membrane proximal external region of gp41, will be rigorously tested and optimized for neutralization-competent structure, functional binding activity, in vitro and in vivo stability, immunogenicity, and HIV-1 neutralizing antibody response. By operating at the interface of chemistry, structural biology, pharmacology, and HIV immunology, we hope to transform HIV-1 from virion to immunogen. As we pass the quarter-century mark of the HIV-1 pandemic, developing an HIV-1 vaccine remains an intractable challenge. We propose that proper education of the immune system will require the development of sturdy and structured immunogens that faithfully reconstitute the virulent conformation of HIV polypeptides. To initiate a new path toward a human HIV-1 vaccine, we will deploy a multidisciplinary strategy to synthesize, characterize, and optimize structurally- reinforced antigens for HIV-1 vaccination using our new hydrocarbon stapling technology that endows natural peptides with bioactive shape and unprecedented stability.

描述（由申请人提供）：艾滋病毒/艾滋病是世界上最重要的人类流行病。从历史上看，引起中和抗体的预防疫苗在减少流行病方面产生了最大的影响。 HIV-1通过避免和破坏宿主免疫系统来挫败现代疫苗技术。临界病毒表位被糖基化掩盖，仅短暂暴露或诱变，无法识别。然而，在这种人类免疫系统失败中，出现了罕见但有效的抗体，这些抗体通过靶向其叶膜融合设备广泛中和HIV-1。因此，尽管历史上未能产生产生临床上有效的抗HIV-1抗体的免疫原子，但我们从那些自然产生的那些相对较少的人类中知道，这一目标在机械上和免疫学上是可以实现的。几种天然抗HIV抗体特异性识别GP41的结构化氨基酸序列，GP41是一种动态融合蛋白，在HIV-1感染过程中采用了构象变化的连续性。在这些表位的结构生物学及其抗体相互作用的新见解的推动下，目前的挑战是重现HIV-1的强大面孔，并将其转变为阿喀琉斯的脚跟。该提案旨在应用一种称为碳氢化合物钉的新型化学技术，既增强了天然肽的生物活性结构，又赋予了前所未有的蛋白酶耐药性，以开发GP41（SAS-GP41）HIV-1疫苗的稳定抗原结构。一旦合成，以GP41的膜近端外部区域进行建模的固定抗原将进行严格测试并优化，以实现中和竞争性结构，功能结合活性，体外和体内和体内稳定性，免疫原性和HIV-1中性抗体抗体反应。通过在化学，结构生物学，药理学和HIV免疫学的界面运行，我们希望将HIV-1从病毒粒子转化为免疫原。当我们通过HIV-1大流行的25年代标记时，开发HIV-1疫苗仍然是一个棘手的挑战。我们建议对免疫系统进行适当的教育，需要开发坚固且结构化的免疫原子，以忠实地重构HIV多肽的强烈构象。为了启动通往人类HIV-1疫苗的新路径，我们将使用我们的新碳氢化合物固定剂技术来综合，表征和优化结构增强的HIV-1疫苗，以赋予天然肽具有生物活性形状和未经前瞻性的稳定性。