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Highly constrained cyclic (S,S) ‐CXaaC‐ peptides as inhibitors of fibrinogen binding to platelets
Author(s) -
KOUKI A.,
MITSIOS J. V.,
SAKARELLOSDAITSIOTIS M.,
SAKARELLOS C.,
TSELEPIS A. D.,
TSIKARIS V.,
TSOUKATOS D. C.
Publication year - 2005
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2005.01487.x
Subject(s) - platelet , peptide , chemistry , integrin , fibrinogen , cyclic peptide , platelet activation , biochemistry , binding site , thrombin , ic50 , biophysics , in vitro , receptor , biology , immunology
Summary. The Arg‐Gly‐Asp RGD motif of adhesive proteins is recognized by the activated platelet integrin α IIb β 3 . Binding of fibrinogen (Fg) to activated α IIb β 3 causes platelet aggregation and thrombus formation. Highly constraint cyclic (S,S) ‐CXaaC‐ containing peptides incorporating the (S,S) ‐CDC‐ and (S,S) ‐CRC‐ motifs were tested for their ability to inhibit platelet aggregation and Fg binding. Our results suggest that the above cyclic scaffolds stabilize a favorable structure for the antiaggregatory activity (IC 50 ‐values ranged from 1.7 to 570 μ m ). The peptides inhibited Fg binding with IC 50 ‐values up to 30‐fold lower than those determined for the inhibition of the adenosine diphosphate (ADP)‐induced platelet aggregation. Importantly, peptides (S,S) PSRCDCR‐NH 2 (peptide 11) and (S,S) PRCDCK‐NH 2 (peptide 10) did not inhibit PAC‐1 binding to the activated platelets at a concentration in which they completely inhibited Fg binding. Moreover, (S,S) PSRCDCR‐NH 2 (peptide 11), one of the more active peptides, inhibited ADP‐induced P‐selectin exposure. By contrast, peptide (S,S) Ac‐RWDCRC‐NH 2 , incorporating the inverse (S,S) ‐DCRC‐ sequence (peptide 16), failed to inhibit P‐selectin exposure whereas at the same concentration, it effectively inhibited PAC‐1 and Fg binding. It is concluded that peptides containing the (S,S) ‐CDC‐ as well the (S,S) ‐CRC‐ sequences, exhibit a broad range of activities toward platelets, and could be helpful tools for elucidating the structural interaction of Fg with the integrin receptor α IIb β 3 , in its activated form. Furthermore, the (S,S) ‐RCDC‐ sequence can be used as a scaffold for developing potent non‐RGD‐like Fg‐binding inhibitors.