Tripeptide SQL Inhibits Platelet Aggregation and Thrombus Formation by Affecting PI3K/Akt Signaling

Abstract

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.

A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3

“…Western blot assay was performed as described by Su and Huang et al [21,22]. Gel-filtered human platelets were preincubated with of TD-26, TGX-221 or vehicle for 10 min and then stimulated by agonists for 5 min with stirring at 37 C. The reaction was stopped by RIPA buffer (1% Triton X-100, 1% deoxycholate, 0.1% SDS, 10 mM Tris, 150 mM NaCl containing protease inhibitors and phosphatase inhibitors).…”

A novel di‐peptide Met‐Glu from collagen hydrolysates inhibits platelet aggregation and thrombus formation via regulation of Gq‐mediated signaling

“…Recently, plenty of antiplatelet inhibitors have been isolated from natural sources (Santhakumar, Stanley, & Singh, 2015; Su, Su, He, Ming, & Kong, 2015; Zhang, Tan, et al, 2018; Zhang, Ma, & Shi, 2018). Collagen peptide is the product of enzymatic degradation of collagen, which usually result in characteristics such as easy absorption, low immunogenicity, safety, and less toxic side effects.…”

Centipede venoms as a source of drug leads

“…For example, a tripeptide (SQL) with antiplatelet activity was isolated from whole-body extracts of S. subspinipes mutilans [17,96]. It has been suggested that SQL might be a useful antithrombotic agent as it inhibits platelet aggregation in vitro and attenuates thrombus formation in vivo, without significant prolongation of bleeding time [17].…”

“…For example, a tripeptide (SQL) with antiplatelet activity was isolated from whole-body extracts of S. subspinipes mutilans [17,96]. It has been suggested that SQL might be a useful antithrombotic agent as it inhibits platelet aggregation in vitro and attenuates thrombus formation in vivo, without significant prolongation of bleeding time [17]. The isolation of three vertebrate-active cardiovascular modulators from venom and whole-body extract of a single centipede species suggests that centipedes might be a richer source of cardiovascular drug leads than would have been anticipated based on their ecology and the limited number of investigations of their venom composition.…”

“…Centipedes are one such group. Despite their use for centuries in traditional medicine [15][16][17], centipede venoms remain poorly studied from a biochemical and pharmacological perspective, and consequently they are underappreciated as a potential source of drug leads.…”