Thioether cross-linked 4E10 peptide epitope from gp41

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.