1 research outputs found
Enhancement of α-Helix Mimicry by an α/β-Peptide Foldamer via Incorporation of a Dense Ionic Side-Chain Array
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