Hybrid peptide design. Hydrogen bonded conformations in peptides containing the stereochemically constrained gamma-amino acid residue, gabapentin.
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 Calpha-Cbeta and Cbeta-Cgamma 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-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-betaLeu-Gpn-Val-OMe 9 and Boc-betaPhe-Gpn-Phe-OMe 10 provide examples of C13 conformation. Gpn peptides provide examples of backbone expanded mimetics for canonical alpha-peptide turns like the gamma (C7) and the beta (C10) turns. The hybrid betagamma sequences provide an example of a mimetic of the C13 alpha-turn formed by three contiguous alpha-amino acid residues. Two examples of folded tripeptide structures, Boc-Gpn-betaPhe-Leu-OMe 11 and Boc-Aib-Gpn-betaPhg-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.
Vasudev
Prema G
PG
Department of Physics, Indian Institute of Science, Bangalore-560012, India.
Ananda
Kuppanna
K
Chatterjee
Sunanda
S
Aravinda
Subrayashastry
S
Shamala
Narayanaswamy
N
Balaram
Padmanabhan
P
D000588:Amines / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry*; D003510:Cyclohexanes / Q000737:chemistry; D000077206:Gabapentin; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000737:chemistry*
D000588:Amines; D000596:Amino Acids; D003509:Cyclohexanecarboxylic Acids; D003510:Cyclohexanes; D010455:Peptides; C506365:Cyclohexane; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin