The Design, Synthesis and Conformation of Some Newβ-Hairpin Mimetics: Novel Reagents for Drug and Vaccine Discovery

Abstract

Syntheses and conformational studies are presented of some novel templates for use in the construction of b-hairpin mimetics. The templates are relatively rigid molecules that constrain the backbone conformation of an attached peptide loop into the bregion of f/y-space. They include diketopiperazines incorporating substituted proline derivatives, as well as heterochiral diproline units, which can be incorporated efficiently into cyclic peptide bhairpin mimetics by solid-phase methods. Potential applications of b-hairpin mimetics in drug and synthetic vaccine discovery are discussed. Figure 2 Two categories of loop are shown, depending on whether the end residues of the b-strands are linked by single (2:4, 3:5, etc. or X:Y loops where Y=X+2) or double H-bonds (2:2, 3:3, etc. or X:Y loops where X=Y), see reference 5 for more details.

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

“…Robinson and co-workers developed a bicyclic building block that can can similarly occupy one of the hairpin turns of antiparallel-β-sheet-like cyclic peptides (e.g., 163 , Figure ). − Compound 163 is notable because the opposing hairpin turn contains the sequence Asn–Pro–Asn–Ala, a key pharmacophore of a malaria protein that is potentially important for vaccine development. Suich and co-workers showed that a biaryl linker can take the place of one of the hairpin turns of the canonical two-turn hexapeptide structure ( 164 , Figure ).…”