The principal secondary structural motifs adopted by peptides assembled from beta-amino acid units are discussed: the 14-, 12-, 10-, 12/10-, and 8-helices, as well as the hairpin turn, extended structures, stacks, and sheets. Features that promote a particular folding propensity are outlined and illustrated by structures determined in solution (NMR) and in the solid-state (x-ray). The N-C(beta)-C(alpha)-CO dihedral angles from molecular dynamics simulations, which are indicative of a particular secondary structure, are presented. A brief description of a helix and a turn of gamma-peptides is also given.

Dedicated to Professor Piero Salvadori, University of Pisa, on the occasion of his 70th birthday Whereas a-peptides are rapidly degraded in vivo and in vitro by a multitude of peptidases, substrates constructed entirely of or incorporating homologated a-amino acid (i.e., b-amino acid) units exhibit a superior stability profile. Efforts made so far to proteolytically hydrolyze a bÀb peptide bond have not proved fruitful; a study aimed at breaching this proteolytic stability is discussed here. A series of such bonds have been designed with side-chain groups similar in relative positions (constitution) and three-dimensional arrangements (configuration) as found about a-peptidic amide bonds. Increasing the prospect for degradation would permit the tuning of b-peptide stability; here, however, no cleavage was observed (1, 2, 4 ± 6, Table 1). Peptides comprised of a-and b-amino acids (mixed a,b-peptides, 8 ± 11) are expected to benefit from both recognition by a natural receptor and a high level of proteolytic stability, ideal characteristics of pharmacologically active compounds. b 3 -Peptides containing a-amino acid moieties at the N-terminus are degraded, albeit slowly, by several peptidases. Of particular interest is the ability of pronase to cleave an aÀb peptide bond, namely that of aAlaÀb 3 hAla. Significantly, successful hydrolysis is independent of the configuration of the b-amino acid. Some of the a,b-peptides discussed here are being investigated for their binding affinities to class I MHC proteins. The computer-programming steps required to prepare a,b-peptides on an automated peptide synthesizer are presented.

One of the benefits of beta-peptides as potential candidates for biological applications is their stability against common peptidases. Attempts have been made to rationalize this stability by altering the electron availability of a given amide carbonyl bond through the introduction of polar substituents at the alpha-position of a single beta-amino acid. Such beta-amino acids (beta-homoglycine, beta-homoalanine), containing one or two fluorine atoms or a hydroxy group in the alpha-position, were prepared in enantiopure form. A versatile method for preparing these alpha-fluoro-beta-amino acids by the homologation of appropriate alpha-amino acids and C-OH->C-F or C=O-->CF(2) substitution with DAST, is described. Consequently, a series of beta-peptides possessing an electronically modified residue at the N terminus or embedded within the chain was synthesized, and their proteolytic stability was investigated against a selection of enzymes. All ten beta-peptides tested were resilient to proteolysis. Introducing a polar, sterically undemanding group, into the alpha-position of beta-amino acids in a beta-peptide chain does not appear to facilitate localized or general enzymatic degradation.

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