SOLID-PHASE SYNTHESIS AND ON-RESIN CYCLIZATION OF A DISULFIDE BOND PEPTIDE AND LACTAM ANALOGS CORRESPONDING TO THE MAJOR ANTIGENIC SITE OF HIV GP41 PROTEIN

A cyclic peptide that spans the major antigenic determinant of the hum an immunodeficiency virus (HIV) glycoprotein 41 (gp41) has been synthe sized according to various strategies. For immunodiagnostic applicatio ns, biotin was added at the N-terminus of the peptide and aminohexanoi c acid was used as a spacer. Polymer-supported oxidations were carried out in a variety of ways with thallium (III) trifluoroacetate. The bi otinylcyclic peptide was released from the support using trimethylsily l trifluoromethane sulfonate and various scavengers. The efficacy of t hese different cyclization and cleavage procedures was compared. Side reactions were studied, and a simple and efficient procedure was set u p to monitor peptide cyclization by mass spectrometry. In a second ser ies of syntheses the disulfide bridge was replaced by an amide bond. F or this purpose, an aspartic acid derivative and a diaminopropionic ac id were introduced during the synthesis in place of the two cysteine r esidues in the parent sequence. On-resin cyclization was performed and led to a major side-product identified as a piperidide. This undesire d base-mediated side reaction was prevented when, instead of piperidin e, 1,8-diazabicyclo-[5.4.0]undec-7-ene was used for fluorenylmethyl es ter deprotection. Reactivity of these peptides with different patients ' sera and with a monoclonal antibody directed against the whole gp41 was tested using an enzyme-linked immunosorbent assay.