Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 71

These examples have demonstrated the power of amide bond modifi-
cations to design novel stable pseudopeptidic agonists and antagonists for
peptide receptors and powerful inhibitors of peptidases.
Another successful backbone modification is the replacement of the
a-carbon by the achiral nitrogen, resulting in azapeptides (Figure 3.23).

R 2

R 2

O

O

N H

N

N

H

H

R 1

R 1

O

O

Figure 3.23 Azapeptide modification

Due to the formation of a rigid urea structure, the rotation around the
C a -C(O) bond (C angle) is greatly reduced in azapeptides. Electronic
repulsions of the lone pairs of the two adjacent nitrogens also restrict
the F angle. Both effects contribute to a reduction of the flexibility of the
backbone. Aza-amino acids were shown to favour the formation of turn
structures [182]. A method for aza-amino acid scanning of a peptide using
Fmoc-solid phase chemistry has been described, and the synthetic strate-
gies were discussed [183]. A large number of aza-analogues of biologically
active peptides have been prepared, including angiotensin II, oxytocin,
enkephalin, GnRH and somatostatin. (see cited refs in [183]). Moreover,
aza-amino acids were shown to be effective building blocks for obtaining
inhibitors of serine or cysteine proteinases: Z-Arg-Leu-Arg-[a-aza-Gly]-Ile-
Val-OMe is the most potent and selective inhibitor of cathepsin B
described [184].
An original approach to develop metabolically stable pseudopeptides
consists of shifting the side chain of an a-amino acid to the a-nitrogen
[185]. This results in N-alkylated glycine oligomers, termed 'peptoids'
[186] (Figure 3.24).
If the original peptide sequence is maintained, the C a to N shift results
in an increased distance between the side chain and the carbonyl group.
This relative distance can be restored by using the reverse peptide
sequence. The peptoid backbone is achiral and exhibits a larger flexibility
than that of a peptide. Both the cis and trans conformations of the back-
bone amide can be significantly populated [187]. Nevertheless, it was
shown that peptoids containing a-chiral aromatic or aliphatic side chains
adopt remarkably stable helical structures, which can mimic the anti-
bacterial activity of magainin [188,189]. Their synthesis can be achieved
either by using preassembled monomeric N-substituted glycines, or by