Novel Synthesis and Application of a Protected Bicyclic α-Helix-Initiating Heptapeptide Suitable for Segment Condensation Syntheses: Utility of Pentaaminecobalt(III) for Carboxyl Protection

Abstract

We have previously demonstrated that incorporation of side-chain lactam linkages between two pairs of lysine and aspartic acid residues placed in the i and i+4 and the i+1 and i+5 positions in a peptide chain generates a fully α-helical structure that is highly resistant to heat denaturation, and is capable of propagating the a-helical conformation in both the N- and C-terminal directions [1]. The synthesis of such helix-initiated peptides is desirable in order to probe the propagation and thermodynamic stability of a helices as a function of their amino-acid sequences. However, the use of solid-phase chemistry to incorporate just one such bicyclic structure into a peptide is highly unreliable, due to the interchain reactions that occur at each attempted intrachain cyclization step. Therefore, we have undertaken the development of a synthetic route to bicyclic helix-initiated peptides that involves the solution-phase preparation of a protected bicyclic peptide segment, 1 (Figure 1), that is suitable for incoporation into a standard Fmoc-based solid-phase synthesis by segment-condensation. This synthetic approach has been demonstrated through the synthesis of an N-terminal helix-initiated analogue of the epitope on the HIV-1 surface glyco-protein gp41 that is recognized by 2F5, an HIV-1 neutralizing monoclonal antibody.