Tetrafibricin: a nonpeptidic fibrinogen receptor inhibitor from Streptomyces neyagawaensis (I). Its GPIIb/IIIa blockage on solid phase binding assay.
Tetrafibricin is a novel nonpeptidic fibrinogen receptor inhibitor isolated from Streptomyces neyagawaensis NR0577. Its competitive and selective fibrinogen receptor blockage was demonstrated in this study. Tetrafibricin competitively inhibited (Ki = 9.9 nM) the binding of biotinylated fibrinogen to purified active glycoprotein (GP) IIb/IIIa immobilized on plastic plate. When RGDS and tetrafibricin were added in combination, the inhibition was additive. The binding of other RGD-containing proteins, fibronectin and von Willebrand factor, to active GPIIb/IIIa were also completely inhibited by tetrafibricin. The fact that tetrafibricin did not inhibit the binding of von Willebrand factor to GPIb/IX indicates the specific blockage of tetrafibricin for GPIIb/IIIa. Fibrinogen receptor inhibition of tetrafibricin was also confirmed by its ability to inhibit 125I-fibrinogen binding to platelets stimulated with ADP. Because of its competitiveness and specificity, tetrafibricin can be used in a new structural model for the design of fibrinogen receptor inhibitors.
Satoh
T
T
Nippon Roche Research Center, Kanagawa, Japan.
Yamashita
Y
Y
Kamiyama
T
T
Watanabe
J
J
Steiner
B
B
Hadváry
P
P
Arisawa
M
M
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018942:Macrolides; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry; D014841:von Willebrand Factor / Q000378:metabolism
D000900:Anti-Bacterial Agents; D018942:Macrolides; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; C027539:fibrinopeptides gamma; D014841:von Willebrand Factor; C082780:tetrafibricin; D000244:Adenosine Diphosphate; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen; C046617:arginyl-glycyl-aspartyl-serine