干细胞之争
体细胞诱导干细胞研究成果之争,专业人士如何评论
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近日,中科院上海药物所在抗幽门螺旋杆菌药物研究方面取得重要进展,发现了一系列具有显著抗幽门螺旋杆菌活性的新化合物,其研究结果发表在最近一期美国《药物化学杂志》(Journal of Medicinal Chemistry)上。
幽门螺杆菌(Helicobacter pylori,Hp)是一种螺旋状厌氧细菌,与慢性胃炎、胃粘膜相关淋巴样组织(MALT)淋巴瘤等疾病的发生都关系密切。Hp感染了世界范围内一半以上的人口,也是目前唯一被确认为胃癌致病因素之一的细菌。脂肪酸是生物体内一类具有十分重要生理活性和生物学功能的物质。β-羟酯酰脱水酶(FabZ)是II型脂肪酸合成途径脂肪酸碳链延长循环阶段中的一个重要的酶,是抗菌药物设计的重要靶标。Hp感染目前主要采用联合用药,但由于易产生严重的副作用,或易产生耐药性,因此,需要寻找更有效的新型药物。
上海药物所沈旭课题组与蒋华良课题组合作,带领博士生张良和刘伟治通过高通量筛选技术发现两个HpFabZ小分子抑制剂,同时解析了HpFabZ和HpFabZ-抑制剂复合物的晶体结构,阐述了FabZ的催化和抑制机制。在此基础上,柳红研究员带领博士生贺凌燕等综合运用药物设计、有机合成、结构生物学和分子细胞生物学方法,发现了一系列具有显著抗幽门螺旋杆菌活性的新化合物。他们设计合成了两个系列的化合物,并测试了对HpFabZ的酶抑制活性,其中有五个化合物的半数抑制浓度小于2 μM,并测定了这五个抑制剂与HpFabZ复合物的晶体结构。为进一步提高活性,他们又针对抑制剂与酶复合物结构,运用组合化学集中库的方法设计了280个小分子,经虚拟筛选及类药性分析,选择了十二个化合物进行了合成和生物测试,结果有八个化合物有较好的活性,阳性率(hit rate)高达66.7%,其中一个化合物的半数抑制浓度为0.86 μM,活性是起始化合物的46倍。
这些研究成果具有重要的学术价值,为基于HpFabZ的药物设计提供了重要的信息,也为运用交叉学科技术进行药物发现研究提供了好的模式。(生物谷Bioon.com)
生物谷推荐原始出处:
Journal of Medicinal Chemistry,52 (8), pp 2465–2481,Xu Shen,Hualiang Jiang
Discovering Potent Inhibitors Against the β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) of Helicobacter pylori: Structure-Based Design, Synthesis, Bioassay, and Crystal Structure Determination
Lingyan He?§, Liang Zhang?§, Xiaofeng Liu?§, Xianghua Li§, Mingyue Zheng§, Honglin Li§, Kunqian Yu§, Kaixian Chen§, Xu Shen*§, Hualiang Jiang*§and Hong Liu*§
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
The discovery of HpFabZ inhibitors is now of special interest in the treatment of various gastric diseases. In this work, three series of derivatives (compounds 3, 4, and 5) were designed, synthesized, and their biological activities were investigated as potential HpFabZ inhibitors in a two phased manner. First, we designed and synthesized two series of derivatives (3a?r and 4a?u) and evaluated the enzyme-based assay against HpFabZ. Five compounds (3i?k, 3m, and 3q) showed potential inhibitory activity, with IC50 values less than 2 μM. Second, a focused combinatorial library containing 280 molecules was designed employing the LD1.0 program. Twelve compounds (5a?l) were selected and synthesized. The activity of the most potent compound 5h (IC50 = 0.86 μM) was 46 times higher than that of the hit 1. The high hit rate and the potency of the new HpFabZ inhibitors demonstrated the efficiency of the strategy for the focused library design and virtual screening.