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Structural and Functional Aspects of RGD-Containing Cyclic Pentapeptides as Highly Potent and Selective Integrin αVβ3 Antagonists
dataset
posted on 1996-08-14, 00:00 authored by Roland Haubner, Rainer Gratias, Beate Diefenbach, Simon L. Goodman, Alfred Jonczyk, Horst KesslerThe αVβ3 integrin is implicated in
human tumor metastasis and in angiogenesis. The design of
low-molecular-mass αVβ3 antagonists by
“spatial screening” led to the highly active peptides
c(RGDFV) and c(RGDFV).
Here the influence of the amino acids in positions 4 and 5
flanking the RGD-sequence on the inhibition of vitronectin
and fibrinogen binding to the isolated αVβ3
and αIIbβ3 receptors was investigated.
The influence of the side chain
and the backbone conformation on activity and selectivity was studied.
The compounds were divided into
conformational classes. For each class at least one representative
peptide was subjected to detailed structure
determination in solution. The peptides of classes 1, 2, and 3
show a βII‘/γ-turn arrangement with the d-amino
acid
in the i + 1 position of the βII‘-turn. By
contrast, the peptides of class 4 reveal a modified βII‘/γ-turn
pattern with
glycine in the i + 1 position of the βII‘-turn and the
d-amino acid in the i + 1 position of the
γ-turn. Class 1 is
divided into two subclasses: besides the βII‘/γ-turn arrangement
a γ/γ-turn motif is found for two members of this
class. Structure−activity relationship (SAR) investigations show
that the amino acid in position 4 and the proton of
the amide bond between residues 3 and 4 are essential for high
biological activities toward αVβ3. By
contrast, the
amino acid in position 5 has no influence on the activity. A bent
conformation of the RGD-sequence, as observed
for the peptides of classes 1 and 2, fits the
αVβ3 better than the
αIIbβ3 receptor and so increases the
selectivity of
these peptides.