Tetrafibricin, a novel non-peptide fibrinogen receptor antagonist, induces conformational changes in glycoprotein IIb/IIIa.
Arg-Gly-Asp (RGD) is an amino acid sequence in fibrinogen recognized by platelet glycoprotein (GP) IIb/IIIa. Recently, it was found that RGD peptide binding to GPIIb/IIIa leads to conformational changes in the complex that are associated with the acquisition of high-affinity fibrinogen-binding function. In this study, we found that tetrafibricin, a novel non-peptidic GPIIb/IIIa antagonist, induced similar conformational changes in GPIIb/IIIa as did RGD peptides. Tetrafibricin increased the binding of purified inactive GPIIb/IIIa to immobilized pl-80, a monoclonal antibody that preferentially recognizes ligand-occupied GPIIb/IIIa. Exposure of the pl-80 epitope by tetrafibricin was also observed on resting human platelets by flow cytometry. On intact platelets, the conformational changes transformed GPIIb/IIIa into a high-affinity receptor for fibrinogen and triggered subsequent platelet aggregation. Tetrafibricin is the first non-peptidic GPIIb/IIIa antagonist reported that has the capacity to induce conformational changes in GPIIb/IIIa.
Satoh
T
T
Nippon Roche Research Center, Kanagawa, Japan.
Kouns
W C
WC
Yamashita
Y
Y
Kamiyama
T
T
Steiner
B
B
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D000939:Epitopes / Q000097:blood; D005340:Fibrinogen / Q000737:chemistry; D006801:Humans; D018942:Macrolides; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000939:Epitopes; D018942:Macrolides; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; C082780:tetrafibricin; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen