Investigation of binding proteins for anti-platelet agent K-134 by Drug-Western method.
K-134 ((-)-6-[3-[3-cyclopropyl-3-[(1R, 2R)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone) is a novel anti-platelet agent with anti-hyperplastic activities. We found previously that K-134 is a potent phosphodiesterase-3 (PDE3) inhibitor. In the present study, we found other K-134-binding proteins by Drug-Western method. We isolated two clones that can bind directly to K-134, cofilin-2, and CD36 in vitro. Comparison of their amino acid sequences showed similarity over a short stretch [KxxxxVxIxWxxE] in part in the collagen-binding region of CD36. K-134 inhibited binding between CD36 and collagen type-I; however, other PDE3 inhibitors, cilostazol, amrinone, and an inactive derivative of K-134, 4S-OH-K-134, showed little or no effect on binding. It was strongly suggested that the direct binding between K-134 and CD36 is a characteristic effect of K-134, and the homologous stretch may be necessary for binding to K-134. These results also suggested that these interactions are involved in the mechanisms of the anti-platelet and anti-hyperplastic effects of K-134.
Ikenoya
Mami
M
Tokyo New Drug Research Laboratories I, Kowa Company, Ltd., Noguchi-cho, Higashimurayama, Tokyo 189-0022, Japan.
Doi
Takeshi
T
Miura
Toru
T
Sawanobori
Kimio
K
Nishio
Masahiro
M
Hidaka
Hiroyoshi
H
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D051340:Cofilin 2 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D018955:CD36 Antigens; D002352:Carrier Proteins; D051340:Cofilin 2; D024042:Collagen Type I; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; D014508:Urea; C116725:OPC 33509