ja068910p_si_002.cif (25.76 kB)

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

Download (25.76 kB)
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.