Gabapentin: A Stereochemically Constrained γ Amino Acid Residue in Hybrid Peptide Design

• Published in: Accounts of chemical research 2009-10, Vol.42 (10), p.1628-1639
• Main Authors: Vasudev, Prema G, Chatterjee, Sunanda, Shamala, Narayanaswamy, Balaram, Padmanabhan
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Cyclohexanecarboxylic Acids - chemistry; Drug Design; gamma-Aminobutyric Acid - chemistry; Hydrogen Bonding; Peptides - chemistry; Protein Conformation; Stereoisomerism
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/ar9001153

Photographs courtesy of Prof. P. Balaram, Indian Institute of Science. Nature has used the all-α-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino acids, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling α-helix and β-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (ω) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino acids with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral β,β-disubstituted γ amino acid residue that contains a cyclohexyl ring at the Cβ carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C−C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical α-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C7 and C9 hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid αγ sequences, distinct C12 hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches α-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer s