Biomedical Engineering Reference
In-Depth Information
O
O
Peptide
Peptide
NH
NH
O
O
O
O
OH
HO
HO
HO
HO
O
7
O
O
HO
HO
6
O
Figure 5.14 Mono- and multifunctionalized b-cyclodextrin. For monofunctiona-
lized cyclodextrin, peptide: H-Trp-Nle-Asp-Phe-NH
2
or H-Ala-Tyr-Gly-Trp-Nle-
Asp-Phe-NH
2
. For heptafunctionalized cyclodextrin, peptide: H-Trp-Nle-Asp-Phe-
NH
2
[79]
forming an amide (Figure 5.14). Next, they prepared the analogous
heptapeptide derivative with an N-terminal extended sequence. Finally,
they anchored seven copies of the tetrapeptide sequence to hepta-(6-
deoxy-6-succinoylamino-)-b-cyclodextrin. After coupling of the pro-
tected peptides, the peptides were deprotected with TFA.
The monoconjugated tetra- and heptapeptides largely retained the
(GPCR) binding and signal transduction efficacy; the additional tripep-
tide in the heptapeptide sequence appeared to mainly function as a
spacer. In contrast, hereto, oligomeric representation in the heptafunc-
tionalized derivative significantly impaired the ligand receptor recogni-
tion process, as the heptaconjugate showed, per peptide moiety, a
significantly reduced binding affinity. The failure of multivalent display
could be due to steric interferences of the peptide moieties, as well as
collapse of the chains on the template. They found indications for bene-
ficial interactions of the b-cyclodextrin moiety with the receptor surface.
The nonspecific binding events make b-cyclodextrins promising as can-
didates for conjugation. These studies were preceded by work in the same
group on the amidation of mono-(6-deoxy-6-succinoylamino-)-b-cyclo-
dextrin with the protease inhibitor H-Leu-Leu-Nle-H [80] They have also
reported the crystal structure of human b-tryptase as a 1 : 2 complex with
b-cyclodextrin difuntionalized with short peptide inhibitors [81]. This
proved the concept of cyclodextrins functioning as scaffolds to control
the distance-geometry in the display of ligands for interaction with multi-
meric protein complexes.
The ability of cyclodextrins to bind hydrophobic guest molecules in
their central cavity has been utilized in the design of novel peptide-based
catalysts as potential enzyme mimetics. In 2000, Ueno and coworkers
reported the synthesis of four 19-mer peptide-b-cyclodextrin hybrids [82].
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