Stapled Antigens for HIV-1 Vaccination

描述(申请人提供)：艾滋病毒/艾滋病是世界上最严重的人类流行病。从历史上看，激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通过躲避和破坏宿主免疫系统，阻碍了现代疫苗技术的发展。关键的病毒表位被糖基化掩盖，只短暂暴露，或者诱变得面目全非。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，通过靶向其膜旁融合装置来广泛中和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，但我们从那些自然产生免疫原的相对罕见的人那里知道，这一目标在机制和免疫学上是可以实现的。几种自然产生的抗HIV抗体特异性地识别gp41的结构氨基酸序列，gp41是一种动态融合蛋白，在HIV-1感染过程中采用一系列构象变化。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，目前的挑战是重建HIV-1的毒力表面并将其转化为阿喀琉斯的脚跟。这项建议旨在应用一种新的化学技术，称为碳氢化合物钉扎，它既增强了天然多肽的生物活性结构，又赋予了前所未有的蛋白酶抗性，以开发稳定的gp41(SAS-gp41)抗原结构，用于HIV-1疫苗接种。一旦合成，模仿gp41膜近端外区的装订抗原将经过严格的中和能力结构、功能结合活性、体外和体内稳定性、免疫原性和HIV-1中和抗体反应的测试和优化。我们希望通过在化学、结构生物学、药理学和HIV免疫学的界面上进行操作，将HIV-1从病毒粒子转化为免疫原。随着我们跨过艾滋病毒-1大流行的四分之一个世纪大关，开发艾滋病毒-1疫苗仍然是一项棘手的挑战。我们认为，对免疫系统的适当教育将需要开发出坚固而有结构的免疫原，以忠实地重建HIV多肽的毒力构象。为了开启人类HIV-1疫苗的新途径，我们将部署多学科战略，利用我们的新碳氢化合物装订技术合成、表征和优化HIV-1疫苗的结构强化抗原，该技术赋予天然多肽以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.