Peptides: Twisting and Turning

Abstract

Oligomers of -amino acids ( -peptides), which are readily available by standard meth­ ods either in solution or on solid support, adopt a large variety of different secondary structures in solution and in the solid state. -Peptides 4, 5 and 10 fold into a helix with 3 residues per turn and 14-membered H-bonded rings (314 helix) that is left-handed for 5 and 10 and right-handed for 2 (due to the reversal of the chirality of the building blocks), as was clearly demonstrated by two-dimensional NMR-spectroscopy. This helix thermally is very stable in methanol solution upon heating. As shown by NMR- and CO-spectroscopy, it is partially populated even at 1oo•c (Figure 3). Another helix was discovered for ,mixed' -peptide 8 in methanol solution: it is characterized by 12- and 10- membered turns (Figure 4, left) and its central 10-membered turn has been found in the solid state of a geminally disubtituted -peptide (Figure 4, right). This central 10-membered turn was used as a scaffold to attach -amino acid residues that prefer a linear (non-helical) conformation ( -peptide 21) : a hairpin (pleated sheet-turn-pleated sheet) structure was determined in solution by NMR-spectroscopy (Figure 5). In contrast to this antiparallel pleated-sheet, a parallel pleated sheet was found for a -tripeptide in the solid state. For the first time it was possible to observe reversible peptide folding in MD simulations by studying -peptides (Figure 6) and to determine folding pathways and intermediates. -Peptides are a new class of promising peptidomimetics. They are resistant against the. degradation by proteolytic enzymes such as pepsin, elastase, carboxypeptidase A, pronase or proteasom 208. A variety of -amino acids (27-34) was shown to be non- mutagenic by Ames' tests and -peptides 47 and 48 reveal large elimination half-lives of 3 h (for 47) and 10 h (for 48) in the serum of rodents (Figure 7). Conjugates of a- and - peptides are efficient ligands for the HLA*B27 MHC Class I protein, a five fold increase of binding (2.0 J.!M for 55) compared to a natural peptidic ligand 51 was observed. Furthermore, -peptides are able to mimic natural a.­ peptidic hormones such as somatostatin. The cyclo- -tetrapeptide 57 binds to the five human somatostatin receptors in the micromolar range. In addition, several other non-natural oligomers such as -peptide nucleic acids (built from 58 and 59), -peptoids (60), oligomers of anthranilic acids and -sulfonamide peptides are discussed.