Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 83

R

O

O OH O

OH N

H
N

H
N COOH

N
H

HNBoc

O

O OH O

HCV NS3 protease

plasmepsin

CH 3

O S

N

NH O

OH

O O

N N

O

Bn

N
H

HN

N

N

HN

O O

O

H

O

O

O

BACE-1 BACE-1

Figure 3.35 Macrocyclic protease inhibitors obtained by RCM reactions

3.4.1.3 Backbone-modified strand mimetics

A different approach to mimicking b-strands is to replace all or part of the
peptide backbone with small carbo- or heterocyclic structures that have the
appropriate geometry and are able to display the functional groups in approxi-
mately the same orientation as in the native b-strand (Figure 3.36). Pioneering
work has been done by Smith and Hirschmann [260], who developed poly-
pyrrolinone b-strand mimetics. This scaffold was used for the preparation of
inhibitors of HIV protease [261], matrix metalloproteases [262] and a hybrid
peptide ligand for the MHC protein HLA-DR1 [263]. The heterochiral
pyrrolinone stereoisomer was shown to adopt a turn conformation, and
provided a somatostatin mimetic with mM potency [264]. The @-Tides frame-
work was proposed by the Bartlett group [265]. In linear oligomers, this unit
was shown to adopt a b-strand conformation and to dimerize. It also induces
b-hairpin folding in attached peptide squences [266]. Peptidomimetics incor-
porating this @-Tides unit have been shown to be potent ligands to a PDZ
protein-interaction domain, with high resistance to protease-mediated degra-
dation [267]. Recently, the aza-@-Tides unit has been developed. It allows
the ready incorporation of a side chain, starting from an amino acid precursor
[268]. A Leu-Gly-Gly b-strand tripeptide mimetic, based on a pyridine
scaffold (R 1 ¼ iPr, R 2 ,R 3 ¼ H),wasrecentlyreported[269].