The application of tetrahydroisoquinoline-3-carbonyl-TARGD(F)F as an anti-thrombotic agent having dual mechanisms of action.
Platelet surface glycoproteins P-selectin and GPIIb/IIIa are implicated in the formation of platelet-fibrin-leukocyte thrombus and platelet-fibrin-platelet thrombus, respectively. In the current study, taking N-(3S-tetrahydroisoquinoline-3-carbonyl)-Thr-Ala-Arg-Gly-Asp-(Phe)-Phe (IQCA-TAFF) as a model compound, the molecular modeling, synthesis, and an evaluation system for a novel anti-thrombotic agent were investigated. The synthesis of IQCA-TAFF was achieved by coupling 3S-tetrahydro-isoquinoline-3-carboxylic acid (IQCA) and Thr-Ala-Arg-Gly-Asp(Phe)-Phe (TAFF). The molecular modeling indicated that IQCA-TAFF was able to occupy the active site pocket of P-selectin with its IQCA moiety and to block GPIIb/IIIa fibrinogen-binding sites with its TAFF moiety, respectively. These are consistent with the dual inhibition of the expressions of P-selectin and GPIIb/IIIa, and with the in vitro anti-platelet aggregation activity of IQCA-TAFF. Besides, the dual suppression of P-selectin and GPIIb/IIIa leads to significant in vivo efficacy of IQCA-TAFF, 500-fold higher than those of IQCA and TAFF, respectively. Transmission electron microscopy (TEM) images indicated that in water, IQCA-TAFF concentration-dependently formed nano-globes. The molecular modeling, in vitro bioassay, in vivo bioassay, action mechanism investigation, and nano-image visualization together constitute a model system to characterize the anti-thrombotic agent capable of simultaneously inhibiting P-selectin and GPIIb/IIIa mediated thrombosis.
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, P.R. China. mingzhao@bjmu.edu.cn
Guodong
G
Yang
Haimei
H
Zhu
Ming
M
Zhao
Jianhui
J
Wu
Yuji
Y
Wang
Yanju
Y
Wang
Meiqing
M
Zheng
Min
M
Chen
Jiawang
J
Liu
Shiqi
S
Peng
D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D019007:P-Selectin / Q000737:chemistry* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000517:prevention & control*
D005343:Fibrinolytic Agents; D007546:Isoquinolines; C577142:N-(3-tetrahydroisoquinoline-3-carbonyl)-threonyl-alanyl-arginyl-glycyl-aspartyl(phenylalanyl)-phenylalanine; D009842:Oligopeptides; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex