ja068910p_si_002.cif (25.76 kB)

Hybrid Peptide Design. Hydrogen Bonded Conformations in Peptides Containing the Stereochemically Constrained γ-Amino Acid Residue, Gabapentin

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posted on 04.04.2007 by Prema G. Vasudev, Kuppanna Ananda, Sunanda Chatterjee, Subrayashastry Aravinda, Narayanaswamy Shamala, Padmanabhan Balaram
The 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 Cα−Cβ and Cβ−Cγ bonds are restricted to the gauche conformation (±60°). 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-Ac6c-Gpn-OMe 1 and Boc-Gpn-Aib-Gpn-Aib-OMe 2 provide examples of C7 conformation; peptides Boc-Gpn-Aib-OH 3, Boc-Ac6c-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 C9 conformation; peptide Boc-Ala-Aib-Gpn-Aib-Ala-OMe 8 provides an example of C12 conformation and peptides Boc-βLeu-Gpn-Val-OMe 9 and Boc-βPhe-Gpn-Phe-OMe 10 provide examples of C13 conformation. Gpn peptides provide examples of backbone expanded mimetics for canonical α-peptide turns like the γ (C7) and the β (C10) turns. The hybrid βγ sequences provide an example of a mimetic of the C13 α-turn formed by three contiguous α-amino acid residues. Two examples of folded tripeptide structures, Boc-Gpn-βPhe-Leu-OMe 11 and Boc-Aib-Gpn-βPhg-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.

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