The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus is associated with necrotizing infections. After binding to complement 5a receptor (C5aR/CD88) and CD45 it causes cytolysis in polymorphonuclear neutrophils (PMNs) as well as inflammasome activation in monocytes. The objective of this study was to test if (ant)agonists of C5aR and CD45 can attenuate the effect of PVL on PMNs and monocytes. We tested the effect of various concentrations of six C5aR (ant)agonists (avacopan, BM213, DF2593A, JPE-1375, PMX205 and W-54011) and one CD45 antagonist (NQ301) to attenuate the cytotoxic effect of PVL on human PMNs and monocytes in vitro. Shifts in the half-maximal effective concentration (EC₅₀) of PVL to achieve a cytotoxic effect on PMNs and modulation of inflammatory cytokine response from monocytes were determined by flow cytometry and IL-1β detection. Pre-treatment of PMNs with avacopan, PMX205 and W-54,011 resulted in 3.6- to 4.3-fold shifts in the EC₅₀ for PVL and were able to suppress IL-1β secretion by human monocytes in the presence of PVL. BM213, DF2593A and NQ301 were unable to change the susceptibility of PMNs towards PVL or reduce inflammasome activation in monocytes. Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1β secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs.

01 Sep 2005·Basic & Clinical Pharmacology & ToxicologyQ3 · MEDICINE

An Antithrombotic Agent, NQ301, Inhibits Thromboxane A₂ Receptor and Synthase Activity in Rabbit Platelets

Q3 · MEDICINE

Article

Author: Lee, Kyung-Sup ; Oh, Ki-Wan ; Cho, Mi-Ra ; Han, Xiang-Hua ; Jin, Yong-Ri ; Lim, Yong ; Yun, Yeo-Pyo ; Hong, Jin-Tae ; Lee, Jung-Jin ; Yoo, Hwan-Soo

Abstract: In previous studies we have reported that NQ301, a synthetic 1,4‐naphthoquinone derivative, displays a potent antithrombotic activity, and that this might be due to antiplatelet effect, which was mediated by the inhibition of cytosolic Ca2+ mobilization in activated platelets. In the present study, the effect of NQ301 on arachidonic acid cascade in activated platelets has been examined. NQ301 concentration‐dependently inhibited washed rabbit platelet aggregation induced by collagen (10 μg/ml), arachidonic acid (100 μM) and U46619 (1 μM), a thromboxane A2 receptor agonist, with IC50 values of 0.60±0.02, 0.78±0.04 and 0.58±0.04 μM, respectively. NQ301 also produced a shift to the right of the concentration‐effect curve of U46619, indicating a competitive type of antagonism on thromboxane A2/prostaglandin H2 receptor. NQ301 slightly inhibited collagen‐induced arachidonic acid liberation. In addition, NQ301 potently suppressed thromboxane B2 formation by platelets that were exposed to arachidonic acid in a concentration‐dependent manner, but had no effect on the production of prostaglandin D2, indicating an inhibitory effect on thromboxane A2 synthase. This was supported by thromboxane A2 synthase activity assay that NQ301 concentration‐dependently inhibited thromboxane B2 formation converted from prostaglandin H2. Moreover, NQ301 concentration‐dependently inhibited 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid formation by platelets that were exposed to arachidonic acid. Taken together, these results suggest that NQ301 has a potential to inhibit thromboxane A2 synthase activity with thromboxane A2/prostaglandin H2 receptor blockade, and modulate arachidonic acid liberation as well as 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid formation in platelets. This may also be a convincing mechanism for the antithrombotic action of NQ301.

01 Jan 2001·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Antiplatelet Effect of 2-Chloro-3-(4-acetophenyl)-amino-1,4-naphthoquinone (NQ301): A Possible Mechanism through Inhibition of Intracellular Ca2+ Mobilization.

Q4 · MEDICINE

Article

Author: LEE, Myung-Koo ; YUN, Yeo-Pyo ; RYU, Chung-Kyu ; CHUNG, Kwang-Hoe ; KO, Myong-Hwa ; ZHANG, Yong-He

The effects of 2-chloro-3-(4-acetophenyl)-amino-1,4-naphthoquinone (NQ301), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein (GP)IIb/IIIa complex and intracellular signals were investigated using human platelets. NQ301 significantly inhibited the collagen-, thrombin-, arachidonic acid-, thapsigargin- and calcium ionophore A23187-induced aggregation of washed human platelets with IC50 values of 13.0+/-0.1, 11.2+/-0.5, 21.0+/-0.9, 3.8+/-0.1 and 46.2+/-0.8 microM, respectively. NQ301 also significantly inhibited FITC-conjugated fibrinogen binding to human platelet surface GPIIb/IIIa complex, but failed to inhibit the fibrinogen binding to purified GPIIb/IIIa complex. These data demonstrate that NQ301 inhibits platelet aggregation by suppression of the intracellular pathway, rather than by direct inhibition of fibrinogen-GPIIb/IIIa complex binding. NQ301 significantly inhibited the increase of cytosolic Ca2+ concentration and ATP secretion, and also significantly increased platelet cAMP levels in the activated platelets. These results suggest that the antiplatelet activity of NQ301 may be mediated by inhibition of cytosolic Ca2+ mobilization, enhancement of cAMP production and inhibition of ATP secretion in activated platelets.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Discovery	KR	Chungbuk National University	-

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