Thioether cross-linked 4E10 peptide epitope from gp41

描述（由申请人提供）：4E10是一种单克隆抗体，来源于持续性HIV感染患者的B细胞。在体外和体内，4E10可以中和多种HIV和SHIV毒株。因此，一种能在人体中引发类似4e10抗体反应的免疫原将是朝着设计一种安全有效的艾滋病疫苗的目标迈出的巨大一步。虽然发现4E10的表位是gp41的融合原结构域的6个氨基酸肽（NWFNIT），但使用该肽作为免疫原来诱导模仿4E10的HIV中和活性的抗体的尝试完全失败。这一结果表明，抗原呈递可能是nwfnit免疫原免疫与体内成功激发4e10样抗体之间缺失的环节。十多年来，我们一直在开发肽化学方法，以诱导线性合成肽产生新的构象。新形成的构象受限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整。利用这种“僵局”技术，我们已经能够从单一的线性肽中形成大量的环状和聚合类似物，所有这些类似物都代表了在母蛋白中发现的肽的可能构象，而母蛋白则是从较小的肽中衍生出来的。本提案的广泛长期目标是使用我们称为Deadlock（tm）技术的新技术创建活性和重要的肽基生物材料的新设计。在申请的资助期内，我们建议开发Deadlock（tm）技术，以创建一种新的基于肽的免疫原，用于引发抗体的艾滋病疫苗。在这项研究中，我们将专注于使用Deadlock（tm）来创建和测试已知是4E10表位的6个氨基酸肽的多种衍生物。成功的免疫原制造类似4e10的抗体的商业机会是巨大的。

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.