Tripeptide SQL Inhibits Platelet Aggregation and Thrombus Formation by Affecting PI3K/Akt Signaling.
Centipede has been prescribed for the treatment of cardiovascular diseases in Asian countries for several hundred years. Previously, a new antiplatelet tripeptide SQL (H-Ser-Gln-Leu-OH) was isolated and characterized from centipede. In this study, we investigated its antithrombotic activities in vivo and underlying mechanism. It was found that SQL inhibited platelet aggregation induced by adenosine diphosphate, thrombin, epinephrine, and collagen and attenuated thrombus formation in both the ferric chloride-induced arterial thrombosis model and arteriovenous shunt thrombosis model in rats. It did not prolong the bleeding time in mice even at the dose of 10 mg/kg that showed potent antithrombosis effects. Molecular docking revealed that SQL binds PI3Kβ with the binding free energy of -24.341 kcal/mol, which is close to that of cocrystallized ligand (-24.220 kcal/mol). Additionally, SQL displayed inhibition on the late (180 seconds) but did not influence the early (60 seconds) Akt Ser473 phosphorylation in the immunoblot assay. These results suggest that SQL inhibits thrombus formation in vivo and that SQL inhibits PI3K-mediated signaling or even the PI3K itself in platelets. This study may help elucidate the mechanism for centipede treating cardiovascular diseases.
*Division of Biopharmaceutical Science, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; †Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, NC; and ‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Xing-li
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Su
Wen
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Zhi-long
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He
Xin
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Ming
Yi
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Kong
D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008024:Ligands; D008815:Mice, Inbred Strains; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*
D005343:Fibrinolytic Agents; D008024:Ligands; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; C000608698:SQL tripeptide; D051057:Proto-Oncogene Proteins c-akt