Hybrid peptide design. Hydrogen bonded conformations in peptides containing the stereochemically constrained gamma-amino acid residue, gabapentin

Vasudev, Prema G and Ananda, Kuppanna and Chatterjee, Sunanda and Aravinda, Subrayashastry and Shamala, Narayanaswamy and Balaram, Padmanabhan (2007) Hybrid peptide design. Hydrogen bonded conformations in peptides containing the stereochemically constrained gamma-amino acid residue, gabapentin. In: Journal of the American Chemical Society, 129 (13). pp. 4039-4048.

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Abstract

he crystal structure of 12 peptides containing the conformationally constrained 1-(aminomethyl)cyclohexaneacetic acid, gabapentin (Gpn), are reported. In all the 39 Gpn residues conformationally characterized so far, the torsion angles about the C-alpha-C-beta and C-beta-C-gamma bonds are restricted to the gauche conformation (+/- 60 degrees). The Gpn residue is constrained to adopt folded conformations resulting in the formation of intramolecularly hydrogen-bonded structures even in short peptides. The peptides Boc-Ac(6)c-Gpn-OMe 1 and Boc-Gpn-Aib-Gpn-Aib-OMe 2 provide examples of C-7 conformation; peptides Boc-Gpn-Aib-OH 3, Boc-Ac(6)c-Gpn-OH 4, Boc-Val-Pro-Gpn-OH 5, Piv-Pro-Gpn-Val-OMe 6, and Boc-Gpn-Gpn-Leu-OMe 7 provide examples of C-9 conformation; peptide Boc-Ala-Aib-Gpn-Aib-Ala-OMe 8 provides an example of C-12 conformation and peptides Boc-beta Leu-Gpn-Val-OMe 9 and Boc-beta Phe-Gpn-Phe-OMe 10 provide examples of C-13 conformation. Gpn peptides provide examples of backbone expanded mimetics for canonical alpha-peptide turns like the gamma (C-7) and the beta (C-10) turns. The hybrid beta gamma sequences provide an example of a mimetic of the C-13 alpha-turn formed by three contiguous alpha-amino acid residues. Two examples of folded tripeptide structures, Boc-Gpn-beta Phe-Leu-OMe 11 and Boc-Aib-Gpn-beta Phg-NHMe 12, lacking internal hydrogen bonds are also presented. An analysis of available Gpn residue conformations provides the basis for future design of folded hybrid peptides.

Item Type:	Journal Article
Publication:	Journal of the American Chemical Society
Publisher:	American Chemical Society
Additional Information:	Copyright of this article belongs to American Chemical Society.
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit Division of Physical & Mathematical Sciences > Physics
Date Deposited:	30 Mar 2010 17:44
Last Modified:	19 Sep 2010 05:57
URI:	http://eprints.iisc.ac.in/id/eprint/26257

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