Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 75

for hydrogen bonding to the receptor, or to another - parallel or antipar-
allel - b-strand. In the latter case, b-sheets are formed. The b-strand is an
important structural element that is preferentially recognized by proteases
and MHC proteins [210,211]. This b-strand conformational selection of
proteases explains the resistance of folded/structured regions of proteins to
proteolytic degradation. Therefore, the fixation of an extended b-strand
ligand conformation should produce high-affinity inhibitors even for pro-
teases of unknown structure [211]. Additionally, b-strand mimetics are
interesting as inhibitors of b-sheet aggregation, a phenomenon which is
associated with a number of neurodegenerative diseases such as
Alzheimer's, Huntington's and Parkinson's diseases and prion potein dis-
eases [212]. Comprehensive reviews on b-strand mimetics up to 2004 have
been published [210,213]. More recently, de Vega reviewed examples up
to 2007 [212].
3.4.1.1 b-sheet nucleating templates
In proteins, antiparallel b-sheet formation is quite often nucleated by
tight turns, resulting in b-hairpin structures. The chain reversal is
achieved by a two-residue nucleus in a b-turn conformation that is
stabilized by a 4 ! 1 hydrogen bond. Several templates for ensuring
polypeptide chain reversal have been developed, and their capability for
inducing b-sheet formation of the attached peptide chains has been
demonstrated. Figure 3.26 shows a representative set of such templates.
In all cases, the templates provide two reactive functional handles which
can be used to attach N- and C-terminal polypeptide chain segments.
The dimensions of the template are chosen such that the pendant anti-
parallel and parallel peptide chains can be brought into hydrogen-
bonding distance, which then facilitates the formation of artificial
b-sheets. For this application, no effort is made to include the original
side chains of the turn unit, which differentiates them from the b-turn
mimics.
The dibenzofuran scaffold with n ¼ 2 was more efficient in stabilizing a
b-sheet structure of the appended peptide sequences than the shorter
analogue with n ¼ 1, provided it was flanked by hydrophobic amino
acids to form the necessary hydrophobic cluster [214] (Figure 3.26). Also,
the 2,3 0 substituted biphenyl required the hydrophobic clustering to
induce the formation of a b-hairpin [215]. This scaffold was used success-
fully in the design of folded peptides that have antiangiogenic activity
[216] or which inhibit the dimerization of HIV-1 protease [217]. The