Hybrid polypeptides: Gabapentin as a steroechemically constrained γ-amino acid residue

Abstract

The design of folded structures in peptides containing the higher homologues of α-amino acid residues requires the restriction of the range of local conformational choices. In α-amino acids stereochemically constrained residues like the α,α-dialkylated residue, aminoisobutyric acid (Aib) and D-Proline (DPro) have proved extremely useful in the design of helices and hairpins in short peptides. Extending this approach, backbone substitution and cyclization are anticipated to be useful in generating conformationally constrained β- and γ-residues. This brief review provides a survey of work on hybrid peptide sequences concerning the conformationally constrained γ-amino acid residue 1-aminomethyl cyclohexane acetic acid, gabapentin (Gpn). This achiral, β,β-disubstituted, γ-residue strongly favors gauche-gauche conformations about the C^α-C^β (θ₂) and C^β-C^γ (θ₁) bonds, facilitating local folding. The Gpn residue can adopt both C₇ (NH_i->CO_i) and C₉ (CO_i-1←NH_i+1) hydrogen bonds which are analogous to the C₅ and C₇ (γ-turn) conformations at α-residues. In conjunction with adjacent residues, Gpn may be used in αγ and γα segments to generate C₁₂ hydrogen bonded conformations which may be considered as expanded analogs of conventional β-turns. The structural characterization of C₁₂ helices, C₁₂/C₁₀ helices with mixed hydrogen bond directionalities and β-hairpins incorporating Gpn residues at the turn segment is illustrated.