The conformational analysis of linear and cyclic peptides incorporating 2,3-methanopipecolic acids (or Cyclopropane Pipecolic Acids, CPAs) as conformationally constrained α-amino acids is reported. Compared to peptides containing proline or pipecolic acid, a striking increase of the cis isomer (42–92%) around the CPA amide bond is observed, both in water and organic solvents, when these unnatural amino acids are embodied in linear amino acid sequences. The rotational barrier around the same bond in water was calculated, giving results comparable to that for the prolyl cis/trans isomerization. In organic solvents, CPAs at the i + 2 position of a peptide induce the formation of a type VIa β-turn secondary structure. When incorporated into a cyclic peptide, the cis geometry around the 2,3-methanopipecolic amide bond still prevails and, in the example studied herein (a cyclic RGD-containing ligand of αVβ3 integrin mimicking Cilengitide), conservation of the backbone geometry and side chain spatial orientation of the native peptide is also found. Given the importance of the proline cis/trans isomerism in many biological processes, CPAs could be useful as proline mimetics for probing protein–ligand interactions and generating novel bioactive compounds.

Synthesis and conformational analysis of peptides embodying 2,3-methanopipecolic acids / L. Ricci, L. Sernissi, D. Scarpi, F. Bianchini, A. Contini, E.G. Occhiato. - In: ORGANIC & BIOMOLECULAR CHEMISTRY. - ISSN 1477-0520. - 15:32(2017 Jul 27), pp. 6826-6836. [10.1039/c7ob01617d]

Synthesis and conformational analysis of peptides embodying 2,3-methanopipecolic acids

A. Contini
Penultimo
;
2017

Abstract

The conformational analysis of linear and cyclic peptides incorporating 2,3-methanopipecolic acids (or Cyclopropane Pipecolic Acids, CPAs) as conformationally constrained α-amino acids is reported. Compared to peptides containing proline or pipecolic acid, a striking increase of the cis isomer (42–92%) around the CPA amide bond is observed, both in water and organic solvents, when these unnatural amino acids are embodied in linear amino acid sequences. The rotational barrier around the same bond in water was calculated, giving results comparable to that for the prolyl cis/trans isomerization. In organic solvents, CPAs at the i + 2 position of a peptide induce the formation of a type VIa β-turn secondary structure. When incorporated into a cyclic peptide, the cis geometry around the 2,3-methanopipecolic amide bond still prevails and, in the example studied herein (a cyclic RGD-containing ligand of αVβ3 integrin mimicking Cilengitide), conservation of the backbone geometry and side chain spatial orientation of the native peptide is also found. Given the importance of the proline cis/trans isomerism in many biological processes, CPAs could be useful as proline mimetics for probing protein–ligand interactions and generating novel bioactive compounds.
peptidomimetics; non natural amino acids; integrin; replica exchange molecular dynamics
Settore CHIM/06 - Chimica Organica
Tumor-targeting peptidomimetics: synthesis and bio-medical applications
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/524059
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