New foldamers and foldamer building blocks

Foldamers are oligomers that have a tendency to adopt a conformationally ordered state in solution. Our lab has long been interested in exploring new kinds of foldamers and new kinds of building blocks to form them. We focus on cyclic constraints at the residue level of our foldamers as a design tool to restrict the conformational freedom of the oligomers and direct the formation of specific secondary structures. To this end, we have developed asymmetric routes to several different cyclically-constrained γ-amino acids, a residue type our lab and others have recently become interested in exploring.

We are also exploring mimicry of the α-helix using peptides composed of α-, β-, and γ-amino acids appropriately patterned to maintain a native-like α residue face for recognition events. We find that replacing the α-peptide heptad repeat with an α/β/γ-peptide hexad repeat, which maintains the number of backbone atoms per two helix turns, provides an α/β/γ-peptide that forms a stable helix in solution. Substitution of one and a half α-helical turns of GCN4pLI, a peptide which forms a four-helix bundle, with an α/β/γ-hexad results in a foldamer that retains the parent α-peptide's self-assembly properties as evidenced by the crystal structure shown below (PDB: 4HJB).

Recent Publications:

  1. "Impact of γ‑Amino Acid Residue Preorganization on α/γ-Peptide Foldamer Helicity in Aqueous Solution." Fisher, B. F.; Gellman, S.H. J. Am. Chem. Soc.  2016, 138, 10766.

  2. "Heterogeneous H-bonding in a foldamer helix." Fisher B.F.; Guo L.; Dolinar B.S.; Guzei I.A.; Gellman S.H. J. Am. Chem. Soc. 2015, 137, 6484.

  3. “New charge-bearing amino acid residues that promote β-sheet secondary structure." Maynard S.J.; Almeida A.M.; Yoshimi Y.; Gellman S.H. J. Am. Chem. Soc. 2014, 136, 16683.

  4.  “A γ-amino acid that favors 12/10-helical secondary structure in α/γ-peptides." Giuliano M.W.; Maynard S.J.; Almeida A.M.; Guo L.; Guzei I.A.; Spencer L.C.; Gellman S.H. J. Am. Chem. Soc. 2014, 136, 15046.

  5. “Evaluation of a Cyclopentane-Based γ-Amino Acid for the Ability to Promote α/γ-Peptide Secondary Structure.” Giuliano M.W.; Maynard S.J.; Almeida A.M.; Reidenbach A.G.; Guo L.; Ulrich E.C.; Guzei I.A.; Gellman S.H. J Org Chem. 2013, 78, 12351.

  6.  "Structural Characterization of Peptide Oligomers Containing (1R,2S)-2-Aminocyclohexanecarboxylic Acid (cis-ACHC)" Choi S.H.; Ivancic M.; Guzei I.A.; Gellman S.H. Eur. J. Org. Chem. 2013, 17, 3464.

  7. “Differential Impact of β and γ Residue Preorganization on α/β/γ-Peptide Helix Stability in Water.” Shin YH, Mortenson DE, Satyshur KA, Forest KT, Gellman SH. J. Am. Chem. Soc. 2013, 135, 8149.