Combinatorial Biomimetic Chemistry: Parallel Synthesis of a Small Library ofβ-Hairpin Mimetics Based on Loop III from Human Platelet-Derived Growth Factor B

Combinatorial diversity in hypervariable β-hairpin loops is exploited by the immune system to select binding sites on antibodies for a wide variety of different protein antigens. In a first step towards mimicking this strategy in vitro, for the selection of novel protein ligands, an approach is described here for the parallel synthesis of small libraries of conformationally defined β-hairpin protein epitope mimetics. Starting from a protruding hairpin loop in platelet-derived growth factor B (PDGF-B), 8 and 12 residues were first transplanted from the protein to a D-Pro-L-Pro template, to afford the cyclic peptide-loop mimetics 1 and 2, respectively. NMR and MD studies in aqueous solution show that both mimetics populate conformations which closely mimic the β-hairpin in the crystal structure of the native protein (Fig. 5). Based on 1 as a scaffold, a library of 24 mimetics was synthesized in which the four residues at the tip of the loop (VRKK) were held constant, and flanking residues at positions 1, 2, 7, and 8 in the hairpin were varied (Fig. 7). The library was prepared by parallel synthesis in a two-stage solid-phase assembly/solution-phase cyclization process. The products were analyzed by MS, NMR, and CD. 2D-NOESY revealed for most library members characteristic long-range NOEs that show that the hairpin conformation is stably maintained. The results suggest that this approach may be useful for the synthesis of much larger libraries of peptide and protein mimetics based on a β-hairpin scaffold.