Biomedical Engineering Reference
In-Depth Information
In another approach, the peptide backbone is preorganized in an
extended form by linking a side chain to the main chain, or a side
chain to a side chain, thus forming a macrocycle [250]. The macro-
cycle prevents intramolecular hydrogen bond formation, and results
in a b-strand conformation of the peptide backbone that is effectively
recognized by proteases [251,252]. Moreover, such macrocycles are
also selective toward other proteases, making them resistant to
degradation. Naturally occurring macrocyclic enzyme inhibitors con-
taining the amino acid isodityrosine as a linking unit are inhibitors of
the metalloproteases angiotensin converting enzyme (ACE) or ami-
nopeptidase N (APN) [250] (Figure 3.34). This has inspired the use
of Tyr as a tool for forming macrocycles, resulting for example in
powerful inhibitors of TNF-a converting enzyme (TACE) [253], HIV
protease [254] and hepatitis C virus (HCV) NS3 protease, as shown
in Figure 3.34 [87].
HO
OH
O
O
O
O
O
O
O
O
H
N
H
N
H
N
HOHN
CH
3
OH
OH
N
H
N
H
N
H
N
H
H
2
N
N
H
O
O
O
O
O
O
H
2
N
O
K-13, ACE
OF4949-IV APN
TAC E
OH
O
O
O
CH
3
O
O
H
N
H
N
N
O
O
N
N
H
CH
3
H
N
H
N
H
N
O
O
O
H
N
H
N
H
O
O
OH
O
O
HIV protease
HCV NS3 protease
Figure 3.34 Macrocyclic protease inhibitors
Ring-closing metathesis (RCM) is also a powerful method for obtaining
various macrocycles (Figure 3.35). Examples shown in Figure 3.35 include
inhibitors of plasmepsin [255], b-secretase (BACE) [256,257] and HCV
NS3 protease [258,259]. These examples convincingly demonstrate that
macrocyclization of peptides is an effective strategy for obtaining b-strand
mimetic protease inhibitors.
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