Thioether cross-linked 4E10 peptide epitope from gp41

来自 gp41 的硫醚交联 4E10 肽表位

• 批准号: 6947131
• 负责人: Frank A. Robey
• 金额: $ 21.84万
• 依托单位: ARIAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947131
• 关键词: HIV envelope protein gp41; antigens; conformation; crosslink; epitope mapping; immunologic substance development /preparation; laboratory rabbit; monoclonal antibody; peptide chemical synthesis; peptide structure; protein structure; synthetic peptide; thioether

DESCRIPTION (provided by applicant): 4E10 is a monoclonal antibody that was derived from the B cells of a patient with persistent HIV infections. In vitro and in vivo, 4E10 neutralizes a wide variety of HIV and SHIV strains. As such, an immunogen that elicits 4E10-like antibody responses in humans would be a huge advance toward the goal of designing a safe and effective vaccine against HIV. Although the epitope for 4E10 was found to be a six amino acid peptide (NWFNIT) from the fusogenic domain of gp41, attempts to use this peptide as an immunogen to elicit antibodies that mimic the HIV neutralizing activity of 4E10 have been totally unsuccessful. This result indicates that antigen presentation is possibly the missing link that lies between immunization with NWFNIT-containing immunogens and the successful elicitation of 4E10-like antibodies in vivo. For over a decade we have been developing methods in peptide chemistry to induce linear synthetic peptides to assume new conformations. The newly-formed conformationally constrained peptides are locked in by stable thioether bonds that would remain intact in intra and extracellular environments rich in degradative enzymes and reducing agents. With this "Deadlock" technology, from a single linear peptide we have been able to form vast numbers of cyclic and polymeric analogs, all representative of possible conformations found for the peptide in a parent protein from which the smaller peptide was derived. The broad long-term objectives of this proposal are to create novel designs of active and significant peptide-based biomaterials using a new technology that we refer to as the Deadlock(tm) technology. During the requested funding period, we propose to develop the Deadlock(tm) technology to create a new peptide-based immunogen for use in an antibody-eliciting AIDS vaccine. For this study, we will focus exclusively on using the Deadlock(tm) to create and test multiple derivatives of a 6 amino acid peptide that is known to be the epitope for 4E10. The commercial opportunities for a successful immunogen to make 4E10-like antibodies is enormous.

描述(申请人提供)：4E10是一种来自持续HIV感染患者的B细胞的单抗。在体外和体内，4E10中和了多种艾滋病毒和新城疫病毒株。因此，在人类体内产生类似4E10的抗体反应的免疫原将是朝着设计安全有效的艾滋病毒疫苗的目标迈进的一大步。尽管4E10的表位被发现是来自gp41融合结构域的六个氨基酸的多肽(NWFNIT)，但试图利用这种多肽作为免疫原来诱导模拟4E10的HIV中和活性的抗体是完全不成功的。这一结果表明，抗原提呈可能是NWFNIT免疫原免疫和体内成功激发4E10类抗体之间缺失的一环。十多年来，我们一直在开发多肽化学方法，以诱导线性合成多肽呈现新的构象。新形成的构象受限的多肽被稳定的硫醚键锁定，在富含降解酶和还原剂的细胞内外环境中保持完好。有了这种“死锁”技术，我们已经能够从单一的线性多肽中形成大量的环状和聚合物类似物，所有这些都代表了在亲本蛋白质中发现的多肽的可能构象，较小的多肽就是从这些构象中衍生出来的。这项提议的广泛长期目标是使用一种我们称为Deadlock(Tm)技术的新技术，创建基于活性和重要多肽的生物材料的新设计。在所要求的资助期内，我们建议开发Deadlock(Tm)技术，以创造一种新的基于多肽的免疫原，用于产生抗体的艾滋病疫苗。在这项研究中，我们将专门使用Deadlock(Tm)来创建和测试已知为4E10表位的6个氨基酸多肽的多个衍生品。一种成功的免疫原制造4E10类抗体的商业机会是巨大的。