一种新型靶向 DprE1 酶抗结核病候选药物 SKLB-TB37
高超1，余洛汀1,*
1四川大学华西医院生物治疗国家重点实验室，四川省成都市人民南路三段17号，610041
*Email: yuluot@
全球每年死于结核病的人数近300万，中国患病人数居世界第二。
由于多重耐药/广谱耐药结核病的出现，现有抗结核病药物已不能满足治愈需求，研发结核新药迫在眉睫[1]。
DprE1 酶作为抗结核药物的新靶点，它能够阻断结核分枝杆菌细胞壁必要组成部分阿拉伯聚糖的合成，从而杀死细菌[2]；该靶点具有特异性、高效性。
本课题组通过基于DprE1 酶的计算机辅助药物设计，合成了大量靶向化合物，经筛选和优化，获得高活性新型分子结构苯并噻嗪-4-硫酮；其中最优先导化合物SKLB-TB37对结核分枝杆菌标准株H37Rv体外MIC99 为 9nM，是一线抗结核药物异烟肼的25倍[3]；对临床分离的多种耐多药菌株及广谱耐药菌株体外MIC99 均达到36nM。
TB37 能够在低剂量下明显抑制结核杆肺部感染，效果优于阳性对照异烟肼。
体外细胞增殖抑制实验显示在高浓度(500μM)下TB37对非洲绿猴肾上皮细胞未表现出毒性，治疗指数大于14400。
在BALB/C小鼠体内最大无毒剂量为5g/kg[4]。
现获得国家十二五“重大新药创制”科技重大专项“候选药物”课题立项（2012ZX09103101-021）。
关键词：结核病；苯并噻嗪硫酮；DprE1酶
参考文献
[1] Anil K.; Eric A.; Nacer L.; Jerome G.. Nature. 2011, 469: 483
[2] Vadim M.; Giulia M.; Katarina M.; Ute M. Science. 2009, 324: 801.
[3] 余洛汀；魏于全. CN 201110139840.2. 2011
[4] 余洛汀；魏于全. PCT/CN2011/075750. 2011
A novel Class1 anti-T
B drug candidate(SKLB-TB37) targeting DprE1 enzyme
Chao Gao1, LuotingYu1,*
1State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,West China
Medical School,Sichuan University,Chengdu,610041
The loss of human lives to tuberculosis(TB) continues essentially unabated as a result of poverty, synergy with the emergence of multi drug-resistant (MDR-TB)and extensively drug-resistant (XDR-TB)strains of Mycobacterium tuberculosis. Hence, faster acting and effective new drugs to better combat TB are needed.DprE1 enzyme is an essential membraneassociated enzyme for arabinose which is a a key precursor that is required for the synthesis of the cell-wall. We have synthesized several series of compounds which designed through the computer-aided drug design base on the DprE1 enzyme .And we obtained benzothiazinethione derivatives which showed potent activity against Mtb.The optimum lead compound SKLB-TB37 showed an MIC of 9nM against H37Rv and 36nM agaist MDR-TB/XDR-TB strains ; A low dose treatment of TB37 inhibited pulmonary infection caused by tubercle bacillus ,the treatment effect is more potent than INH. In vitro/In vivo toxicology tests revealed no particularly unfavorable effects.。