日前，南京医科大学朱东亚教授与其科技团队在美国《NatureMedicine》杂志发表了题为《阻断缺血诱导的nNOS与PSD95相互作用**脑缺血损伤》的论文，提出了一个**脑中风的新**作用靶点，进而研究出了一种小分子**。由于这种新药既能够起到有效的**作用，又避免了目前其他**普遍存在的副作用过大的缺陷，《NatureMedicine》杂志社特邀该领域的科学家为此发表评论，称“小分子**ZL-006的出现让我们看到了脑卒中等神经系统****的新曙光”。脑卒中，俗称脑中风，在我国的发病率高居所有病症的前三位，这种**发病率高且后遗症多（包括偏瘫、认知障碍等）。如何才能找到一种疗效好又无副作用的抗脑卒中**，是国际医学界多年来悬而未决的重要课题。在多年研究的基础上，一次独辟蹊径的设想使朱东亚将研究的目光从抑制靶标本身移向了“下游”——细胞内蛋白与蛋白的相互作用。从蛋白间结合的角度进行抗脑卒中**的研究非常困难，在世界范围也鲜有先例可循。在仔细研究了两种蛋白的性质和结构的基础上，朱东亚设计了一百多种化合物，并*终筛选出了“ZL—006”——一种一端亲水另一端疏水的小分子化合物。通过动物及细胞实验验证，该化合物确实可以阻断两蛋白的结合，而且在若干种脑卒中模型中都显示了它的疗效，更为重要的是，实验已经证实这种**不会影响认知、学习和记忆，也不会导致动物具有进攻性等行为异常，它不具有其他**针对受体的副作用。 Stroke is a major public health problem leading to high rates ofdeath and disability in *****s1, 2. Excessive stimulation ofN-methyl-D-aspartate receptors (NMDARs) and the resulting neuronalnitric oxide synthase (nNOS) activation are crucial for neuronalinjury after stroke insult3, 4, 5, 6, 7. However, directlyinhibiting NMDARs or nNOS can cause severe side effects becausethey have key physiological functions in the CNS5, 8, 9, 10, 11,12. Here we show that cerebral ischemia induces the interaction ofnNOS with postsynaptic density protein-95 (PSD-95). DisruptingnNOS–PSD-95 interaction via overexpressing the N-terminal aminoacid residues 1–133 of nNOS (nNOS-N1–133) preventedglutamate-induced excitotoxicity and cerebral ischemic damage.Given the mechanism of nNOS–PSD-95 interaction, we developed aseries of compounds and discovered a small-molecular inhibitor ofthe nNOS-PSD-95 interaction, ZL006. This drug blocked theischemia-induced nNOS–PSD-95 association selectively, had potentneuroprotective activity in vitro and ameliorated focal cerebralischemic damage in mice and rats subjected to middle cerebralartery occlusion (MCAO) and reperfusion. Moreover, it readilycrossed the blood-brain barrier, did not inhibit NMDAR function,catalytic activity of nNOS or spatial memory, and had no effect onaggressive behaviors. Thus, this new drug may serve as a treatmentfor stroke, perhaps without major side effects.本文章转载:http://www.rryangsheng.com/Frontiers/131221_01.html