Enhancement of α-helix mimicry by an α/β-peptide foldamer via incorporation of a dense ionic side-chain array Academic Article uri icon


MeSH Major

  • HIV
  • HIV Envelope Protein gp41
  • Peptides


  • We report a new method for preorganization of α/β-peptide helices, based on the use of a dense array of acidic and basic side chains. Previously we have used cyclically constrained β residues to promote α/β-peptide helicity; here we show that an engineered ion pair array can be comparably effective, as indicated by mimicry of the CHR domain of HIV protein gp41. The new design is effective in biochemical and cell-based infectivity assays; however, the resulting α/β-peptide is susceptible to proteolysis. This susceptibility was addressed via introduction of a few cyclic β residues near the cleavage site, to produce the most stable, effective α/β-peptide gp41 CHR analogue identified. Crystal structures of an α- and α/β-peptide (each involved in a gp41-mimetic helix bundle) that contain the dense acid/base residue array manifest disorder in the ionic side chains, but there is little side-chain disorder in analogous α- and α/β-peptide structures with a sparser ionic side-chain array. These observations suggest that dense arrays of complementary acidic and basic residues can provide conformational stabilization via Coulombic attractions that do not require entropically costly ordering of side chains.

publication date

  • May 2, 2012



  • Academic Article



  • eng

PubMed Central ID

  • PMC3377471

Digital Object Identifier (DOI)

  • 10.1021/ja302428d

PubMed ID

  • 22524614

Additional Document Info

start page

  • 7317

end page

  • 20


  • 134


  • 17