The application of tetrahydroisoquinoline-3-carbonyl-TARGD(F)F as an anti-thrombotic agent having dual mechanisms of action

Mol Biosyst. 2012 Oct;8(10):2672-9. doi: 10.1039/c2mb25112d.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Blood Platelets / drug effects*
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / metabolism
  • Fibrinolytic Agents / pharmacology
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology
  • Male
  • Microscopy, Electron, Transmission
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology
  • P-Selectin / chemistry*
  • P-Selectin / metabolism
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Glycoprotein GPIIb-IIIa Complex / chemistry*
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Protein Binding
  • Protein Conformation
  • Rats
  • Rats, Wistar
  • Thrombosis / prevention & control*

Substances

  • Fibrinolytic Agents
  • Isoquinolines
  • N-(3-tetrahydroisoquinoline-3-carbonyl)-threonyl-alanyl-arginyl-glycyl-aspartyl(phenylalanyl)-phenylalanine
  • Oligopeptides
  • P-Selectin
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex