Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 88

The Bartlett group described the hexahydroindol-4-one diacid and
the diamino-substituted diazabicyclo[4,3,0]nonene amidinium salt as
helix nucleators [304,305]. In the latter, the three NH hydrogen-bond
donors are positioned in an ananalogous arrangement to the three
carbonyl group hydrogen-bond acceptors of the N-terminal diacid
template and therefore could mimic the hydrogen-bonding pattern of
the first turn at the C-terminus of an a-helix. This remains to be demon-
strated, however.

3.4.2.2 Helix surface mimetics

A number of approaches to develop nonpeptide a-helix mimetics have
been described. Side chains along one face of a helix are often respon-
sible for critical interactions with the target proteins. 1,1,6-
Trisubstituted indanes reported by Horwell and coworkers are used
to represent amino acids at the i and i þ 1 positions of an a-helix
(Figure 3.41). The designed mimetics of dipeptides (Phe-Phe and Trp-
Phe) using this scaffold show micromolar affinity similar to the original
dipeptides, in an attempt to mimic tachykinins and other neuropeptide
targets [306]. However, the indanes can mimic only two amino acids,
and therefore are not suitable for covering more residues in a helix.
Jacoby suggested 2,6,3 0 ,5,-tetrasubstituted biphenyl analogues to
mimic one helical turn [307]. Hamilton and coworkers have reported
scaffolds which can represent two helical turns. Trifunctionalized
3,2 0 ,2 00 -terphenyl derivatives hold side chains located at the i , i þ 3or
i þ 4, and i þ 7 positions [224] in two helical turns. When fitted with the
appropriate side chains, these helix surface mimics were found to effec-
tively disrupt the interactions between calmodulin and smooth muscle
light-chain kinase [308], between Bcl-x L and Bak proteins [309,310],
and between the p53 protein and MDM2 [311], and also to inhibit the
self-assembly of a six-helix bundle gp41 core [312], demonstrating
thepotentialuseofa-helix mimetics as therapeutics. In order to be
able to exploit additional interactions by residues adjacent to those
forming the hydrophobic face of the helix, the Hamilton group designed
the 4,7-diphenyl-substituted indane scaffold, which can display the i ,
i þ 3, i þ 4and i þ 7 side chains, thereby mimicking two faces of a
helix [313].
A tris-pyridylamide scaffold was also designed to display side chains
found at the i , i þ 4 and i þ 7 positions, in order to inhibit the formation
of a Bak BH3/Bcl-xL complex [314]. Recently, Ahn and coworkers