Development of a novel anti-platelet drug targeted for collagen-induced platelet aggregation

AAPP是一种蚊子唾液蛋白，通过直接与胶原蛋白结合，导致血小板聚集，特异性地阻断血小板与胶原蛋白的粘附。本研究的目的是确定AAPP负责抗血栓活性的活性区域，因为我们假设AAPP可以用作候选抗血小板药物。我们发现AAPP的胶原结合和抗血栓活性的基本部分位于外显子3-4编码的区域。测定了该畴的晶体结构。AAPP对10 mg/kg体重的胶原诱导的全血聚集有抑制作用。与阿司匹林（100 mg/kg）相比，AAPP以较低剂量（3 mg/kg）预防肺死亡，而不会延长出血时间，后者会损害止血。这些结果表明，AAPP作为一种新的抗血小板药物具有很大的潜力，其风险/效益比优于阿司匹林。

AAPP, a mosquito saliva protein, specifically blocks platelet adhesion to collagen by binding directly to collagen and subsequently causing platelet aggregation. The aim of this study was to identify the active region of AAPP responsible for the anti-thrombotic activity because we hypothesized that AAPP could be used as a candidate anti-platelet drug. We identified that the essential moiety of AAPP for collagen binding and anti-thrombotic activity was in the region encoded by exon 3-4. The crystal structure of this domain was also determined. AAPP inhibited whole blood aggregation induced by collagen at 10 mg/kg body weight. AAPP prevented pulmonary death at a lower dose (3 mg/kg) without prolongation of bleeding time compared with aspirin (100 mg/kg) that compromised hemostasis. These results indicate that AAPP has great potential as a new anti-platelet agent with a better risk/benefit ratio than that seen with aspirin.