The Proteolytic Stability of ‘Designed’β-Peptides Containingα-Peptide-Bond Mimics and of Mixedα,β-Peptides: Application to the Construction of MHC-Binding Peptides

Abstract

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.

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

“…S8A). It has been proposed that the introduction of β-amino acids into the peptides provides increased resistance to hydrolysis and contributes to their stability in biological systems (32,33). Additionally, the gichigamins lack both glutamine (Gln) and glutamic acid (Glu) residues, which Ac U P U P F J…”

“…The resulting products were purified, structurally characterized, and tested for cytotoxicity to gain further insights into the relationships between the primary and secondary structural features of the gichigamins and their biological properties. Nine major products were obtained (24)(25)(26)(27)(28)(29)(30)(31)(32) from the hydrolysis of 1 (SI Appendix, Fig. S3A) and ECD spectra were collected and analyzed for each compound (SI Appendix, Fig.…”

Imaging of aβ-peptide distribution in whole-body mice sections by MALDI mass spectrometry

“…With the high sensitivity of MALDI MS in ␣ the peptide mass range, it is an obvious choice to apply MALDI MS imaging to the study of the distribution of ␤-peptides as reported here. We therefore chose two ␤ peptides (Figure 1), formerly used in the study of class 1 MHC peptide mimics, as representative examples of a ␤-and an ␤ ␣-peptide ␣ [12].…”

“…␤ ␤ hLys-OH) was prepared by solid-phase-peptide-synthesis according to [12]. ␣-Peptide ␣ ␣ 2 (Rheuma peptide Ser-Arg-His-His-Ala-PheCys-Phe-Arg) was purchased from NeoMPS (San Diego, CA).…”

Molecular mimicry of conformationally diverse β-sheets by using α/β-peptide foldamers

“…29 Furthermore, proteolytic enzymes cannot recognize -peptides [30][31] and the replacement of around 30% of the residues to -amino acids in a peptidic sequence dramatically increases the stability against proteases. [32][33][34] Pharmacokinetic studies revealed elimination half-lives of 3-10 h which is significantly longer than that of an -peptidic sequence. proteogenic side-chain on the  or  carbon atom respectively, and the synthesis of these building blocks are generally straightforward.…”