Stapled Antigens for HIV-1 Vaccination

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，引发中和抗体的预防性疫苗在遏制流行病方面取得了最大的影响。HIV-1通过逃避和破坏宿主免疫系统而挫败了现代疫苗技术。关键的病毒表位被糖基化所掩盖，仅短暂暴露，或诱变而无法识别。然而，在这种人类免疫系统的失败中，出现了罕见但有效的抗体，通过靶向其质膜融合装置广泛中和HIV-1。因此，尽管历史上未能产生引发临床有效的抗HIV-1抗体的免疫原，但我们从那些自然产生它们的相对罕见的人类中知道，这一目标在机械上和免疫学上是可以实现的。几种天然存在的抗HIV抗体特异性识别gp 41的结构化氨基酸序列，gp 41是一种动态融合蛋白，在HIV-1感染过程中采用连续的构象变化。在这些表位及其抗体相互作用的结构生物学的新见解的推动下，目前的挑战是重新创建HIV-1的毒性，并将其转变为阿基里斯之踵。该提案旨在应用一种新的化学技术，称为碳氢化合物钉合，该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抗性，以开发用于HIV-1疫苗接种的稳定的gp 41抗原结构（SAS-gp 41）。一旦合成，在gp 41的膜近端外部区域之后建模的钉合抗原将针对中和能力结构、功能结合活性、体外和体内稳定性、免疫原性和HIV-1中和抗体应答进行严格测试和优化。通过在化学、结构生物学、药理学和HIV免疫学的界面上操作，我们希望将HIV-1从病毒体转化为免疫原。在我们度过艾滋病毒-1大流行的四分之一世纪之际，开发艾滋病毒-1疫苗仍然是一项棘手的挑战。我们建议，适当的教育的免疫系统将需要发展坚固的和结构化的免疫原，忠实地重建HIV多肽的毒性构象。为了开创人类HIV-1疫苗的新途径，我们将采用多学科策略，利用我们的新型碳氢化合物钉合技术合成、表征和优化HIV-1疫苗的结构增强抗原，该技术赋予天然肽生物活性形状和前所未有的稳定性。

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.