Probing the Proteolytic Stability of β‐Peptides Containing α‐Fluoro‐ and α‐Hydroxy‐β‐Amino Acids

Hook, David; Gessier, François; Noti, Christian; Kast, Peter; Seebàch, Dieter

doi:10.1002/cbic.200300827

Cited by 130 publications

(73 citation statements)

References 51 publications

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“…As expected, based on the lack of net positive charge, none of these peptides displayed antibacterial activity. One interesting observation among this set of peptides is the difference in hemolytic activity between the epimeric 2-hydroxy peptides 14 and 15 [25]. The configuration of the stereogenic center bearing the OH group exerts a major influence on the structures of these two peptides; whereas 15 (of unlike-configuration) adopts a 3 14 -helix, the like-configured compound 14 exhibited no helical conformation (NMR investigation [43]).…”

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confidence: 96%

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Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β²‐3‐Aza‐ and β³‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

Arvidsson

Ryder²,

Weiss

et al. 2005

Chemistry & Biodiversity

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The antibacterial activities of 31 different beta-, mixed alpha/beta-, and gamma-peptides, as well as of beta-peptides derived from beta2-3-aza- and beta3-2-methylidene-amino acids were assayed against six pathogens (Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa), and the results were compared with literature data. The interaction of these peptides with mammalian cells, as modeled by measuring the hemolysis of human erythrocytes, was also investigated. In addition to those peptides designed to fold into amphiphilic helical conformations with positive charges on one face of the helix, one new peptide with hemolytic activity was detected within the sample set. Moreover, it was demonstrated that neither cationic peptides used for membrane translocation (beta3-oligoarginines), nor mixed alpha/beta- or gamma-peptides with somatostatin-mimicking activities display unwanted hemolytic activity.

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“…Likewise, peptide 11, which also contains a disubstituted b-amino acid of like-configuration, showed no helical NMR structure, with peptides 12 and 13 assuming the 3 14 -helix [43] [44]. Such F-and OH-containing b-peptides have been used for studies aimed at understanding the proteolytic stability of b-peptides [25].…”

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confidence: 98%

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β²‐3‐Aza‐ and β³‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

Arvidsson

Ryder²,

Weiss

et al. 2005

Chemistry & Biodiversity

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“…The introduction of electronwithdrawing groups adjacent to the CO functionality of a b-peptidic bond failed to facilitate proteolytic degradation [8]. Consequently, a lack of recognition resulting from the distinct spatial and/or configurational arrangements of side-chain groups, the structural orientation of the backbone or other inherent recognition features appears to account for the stability of b-peptides towards proteolytic action.…”

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confidence: 97%

“…[8]. ± The palette of peptidases selected for this study was aimed at representing a broad range of cleavage-site preferences [31].…”

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confidence: 99%

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

Hook

Bindschädler

Mahajan

et al. 2005

C&B

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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.

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“…1, a) [30] [31]. The bheptapeptide 1 with a central bhAla(a-Me) unit of like configuration has been shown by CD and NMR analysis [30], as well as by molecular-dynamics simulation [32 ± 36] to form an especially stable 3 14 -helix, with the two Me groups in lateral positions (Fig.…”

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The Effect of Backbone-Heteroatom Substitution on the Folding of Peptides - A Single Fluorine Substituent Prevents a?-Heptapeptide from Folding into a314-Helix (NMR Analysis)

Mathad

Gessier

Seebàch³

et al. 2005

HCA

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acid residues (bhAla(X n )) of like and unlike configuration were subjected to a detailed NMR analysis in MeOH solution. For the geminal difluoro and for the F-and OH-substituted derivatives of u-configuration (see 5, 4, and 7, resp.), 14-helices were found, i.e., with axial disposition of the hetero atoms on the helix. The two compounds containing the central l-configured b-amino acid moieties (see 3 and 6) are not helical over the full lengths of the chains; they have quasi-helical termini and a central turn consisting of a ten-membered H-bonded ring (Fig. 2, d and e). Quantum-mechanical calculations with l-and u-AcNH-CHMe-CHF-CONH 2 confirm the observed preference for a conformation with antiperiplanar arrangement of the FÀC and the CO bond. The calculated energy difference between the observed non-helical geometry of this moiety and a hypothetical helical one is 6.4 kcal/mol (Fig. 3).

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Probing the Proteolytic Stability of β‐Peptides Containing α‐Fluoro‐ and α‐Hydroxy‐β‐Amino Acids

Cited by 130 publications

References 51 publications

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β²‐3‐Aza‐ and β³‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β²‐3‐Aza‐ and β³‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

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

The Effect of Backbone-Heteroatom Substitution on the Folding of Peptides - A Single Fluorine Substituent Prevents a?-Heptapeptide from Folding into a314-Helix (NMR Analysis)

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Probing the Proteolytic Stability of β‐Peptides Containing α‐Fluoro‐ and α‐Hydroxy‐β‐Amino Acids

Cited by 130 publications

References 51 publications

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β2‐3‐Aza‐ and β3‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β2‐3‐Aza‐ and β3‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

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

The Effect of Backbone-Heteroatom Substitution on the Folding of Peptides - A Single Fluorine Substituent Prevents a?-Heptapeptide from Folding into a314-Helix (NMR Analysis)

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Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β²‐3‐Aza‐ and β³‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey

Exploring the Antibacterial and Hemolytic Activity of Shorter‐ and Longer‐Chain β‐, α,β‐, and γ‐Peptides, and of β‐Peptides from β²‐3‐Aza‐ and β³‐2‐Methylidene‐amino Acids Bearing Proteinogenic Side Chains – A Survey