beta-peptides: Twisting and turning

Oligomers of beta-amino acids (beta-peptides), which are readily available by standard methods either in solution or on solid support, adopt a large v ariety of different secondary structures in solution and in the solid state . beta-Peptides 4, 5 and 10 fold into a helix with 3 residues per turn and 14-membered H-bonded rings (3(14) helix) that is left-handed for 5 and 10 a nd 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 s hown by NMR- and CD-spectroscopy, it is partially populated even at 100 deg rees C (Figure 3). Another helix was discovered for, mixed' beta-peptide 8 in methanol solution: it is characterized by 12- and 10- membered turns (Fi gure 4, left) and its central 10-membered turn has been found in the solid state of a geminally disubtituted beta-peptide (Figure 4, right). This cent ral 10-membered turn was used as a scaffold to attach beta-amino acid resid ues that prefer a linear (non-helical) conformation (beta-peptide 21): a ha irpin (pleated sheet-turn-pleated sheet) structure was determined in soluti on by NMR-spectroscopy (Figure 5). In contrast to this antiparallel pleated -sheet, a parallel pleated sheet was found for a beta-tripeptide in the sol id state. For the first time it was possible to observe reversible peptide folding in MD simulations by studying beta-peptides (Figure 6) and to deter mine folding pathways and intermediates. beta-Peptides are a new class of promising peptidomimetics. They are resist ant against the degradation by proteolytic enzymes such as pepsin, elastase , carboxypeptidase A, pronase or proteasom 20S. A variety of beta-amino aci ds (27-34) was shown to be non- mutagenic by Ames tests and beta-peptides 4 7 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 alpha- and beta- pept ides are efficient ligands for the HLA*B27 MHC Class I protein, a five fold increase of binding (2.0 mu M for 55) compared to a natural peptidic ligan d 51 was observed. Furthermore, beta-peptides are able to mimic natural alp ha-peptidic hormones such as somatostatin. The cyclo-beta-tetrapeptide 57 b inds to the five human somatostatin receptors in the micromolar range. In addition, several other non-natural oligomers such as beta-peptide nucle ic acids (built from 58 and 59), beta-peptoids (60), oligomers of anthranil ic acids and beta-sulfonamido peptides are discussed.