Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 81

It is interesting to note that Fmoc-Hao was shown to inhibit the
dimerization of HIV protease [217].

3.4.1.2 Macrocyclic b-strand mimics

b-hairpins are widely-occurring secondary structural elements in
proteins, consisting of two adjacent strands of antiparallel b-sheet
and a connecting loop. Cross-strand hydrogen bonding usually sta-
bilizes b-hairpin structures. The shortest common loop involves two
residues, in which case the loop and the two adjacent residues
constitute a b-turn [240]. Based on the work of Marshall [224],
showing that the D -Pro- L -Pro sequence (Figure 3.26) is a strong
reverse turn inducer, the Robinson group has developed a strategy
for the design of b-hairpin mimetic cyclic peptides by using this
sequence to connect the N- and C-termini of the hairpin part of the
native protein [223,241] (Figure 3.33). This sequence is a strong
turn inducer and was shown to be able to maintain the b-hairpin
conformation in many attached loops. This strategy allowed the
preparation of b-hairpin mimetics as trypsin inhibitors [242],
CXCR4 inhibitors [243], antimicrobial peptides [244], peptides
binding to a human antibody [245] or inhibitors of the Tat-TAR
interaction of bovine immunodeficiency virus [246]. Interestingly,
the b-hairpin scaffold can be used to preorganize the side chains in
a geometry similar to that seen in a helical peptide (see Section
3.4.2) [247,248]. Biaryl amino acid templates were shown to be less
effective in promoting b-hairpin conformations than the D -Pro- L -Pro
sequence, although the resulting cyclic analogues of protegrin 1
retained significant antimicrobial activity [249].

O

N

β -strand

β -strand

O

protein

O

H

N NH β -strand

β -strand

N

O

Figure 3.33 Template-bound hairpin mimetic or b-hairpin protein epitope mimetics
(PEM)