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，引起中和抗体的预防性疫苗在减少流行病方面取得了最大的影响。HIV-1通过躲避和破坏宿主免疫系统，挫败了现代疫苗技术。关键的病毒表位被糖基化掩盖，仅短暂暴露，或突变而无法识别。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，通过靶向其近膜融合装置广泛中和HIV-1。因此，尽管历史上未能产生产生临床有效的抗hiv -1抗体的免疫原，但我们从那些相对罕见的自然产生它们的人类中知道，这一目标在机械和免疫上是可以实现的。几种自然产生的抗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感染过程中采用连续的构象变化。在这些表位结构生物学及其抗体相互作用的新见解的推动下，目前的挑战是重建HIV-1的毒性面孔并将其转化为阿喀琉斯之踵。本研究旨在应用一种新的化学技术，即碳氢化合物钉接技术，增强天然肽的生物活性结构，并赋予前所未有的蛋白酶抗性，以开发稳定的gp41抗原结构（SAS-gp41），用于HIV-1疫苗接种。一旦合成，以gp41的膜近端外区为模型，将进行严格的测试和优化，以确定中和能力结构、功能结合活性、体外和体内稳定性、免疫原性和HIV-1中和抗体反应。我们希望通过化学、结构生物学、药理学和HIV免疫学的交叉作用，将HIV-1从病毒粒子转化为免疫原。随着我们走过艾滋病毒-1大流行的四分之一个世纪，研制艾滋病毒-1疫苗仍然是一项棘手的挑战。我们建议，适当的免疫系统教育将需要发展坚固和结构化的免疫原，忠实地重建HIV多肽的毒力构象。为了开创人类HIV-1疫苗的新途径，我们将采用多学科策略，利用我们新的碳氢化合物钉接技术合成、表征和优化用于HIV-1疫苗接种的结构增强抗原，该技术赋予天然肽具有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.