Biomedical Engineering Reference
In-Depth Information
clear that these concepts have a proven value in peptide design, and their
application constitutes an interesting step toward the transformation of a
peptide into a peptide mimetic.
3.3
PSEUDOPEPTIDES
The observation that the metabolic breakdown of peptides occurs
through enzyme-catalysed hydrolysis of the peptide bonds has been a
primary motivation for the replacement of the scissile amide bonds by
nonhydrolysable isosteres (Figure 3.16). Such isosteres were at the basis
of the development of transition state analogue enzyme inhibitors,
which led to a breakthrough in the development of inhibitors for several
therapeutically important enzymes. Moreover, peptide chemists
realized that it was important to investigate whether the backbone
had a functional role or just served to orient and align the side chains
[123]. In the latter case, the transposition of the side-chain groups from
the a-carbontothea-nitrogen, resulting in N-peptoids, seems a logical
step. Other backbone modifications include the replacement of the
a-carbon by, for instance, a nitrogen, leading to achiral azapeptides.
In addition, the insertion of extra atoms into the backbone chain by
using b-homo amino acids, g-amino acids or even longer-chain amino
acids has been explored.
replace
α
-carbon:
α
-aza-amino acid
modify amide bond: pseudo peptide bond
move side chain to N:
N
-peptoid
O
H
N
H
N
N
H
O
O
2
-homo amino acid, vinylogous
insert atom(s):
β
insert atom(s):
β
3
-homo amino acid,
γ
-amino acid, urea analogue
amino acid,
Figure 3.16 Examples of strategies used in pseudopeptide design
Many amide bond replacements have been developed over the years.
Some representative examples are given in Figure 3.17. Modifications of
the amide function include a change at the nitrogen, at the carbonyl, or at
both positions. The change of the amide bond is indicated by the symbol C,
as an indication of a pseudo-amide function, while the replacing function is
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