A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.
A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.
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DOI：
10.1021/acs.jmedchem.8b00884
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发表时间：
2018-09-27
影响因子：
7.3
通讯作者：
Read KD
中科院分区：
文献类型：
--
作者：
Harrison JR;Brand S;Smith V;Robinson DA;Thompson S;Smith A;Davies K;Mok N;Torrie LS;Collie I;Hallyburton I;Norval S;Simeons FRC;Stojanovski L;Frearson JA;Brenk R;Wyatt PG;Gilbert IH;Read KD
晶体学指导了两个系列布氏锥虫 N-肉豆蔻酰转移酶 (NMT) 抑制剂的杂交，从而产生了一个新型的高选择性系列。结合两个药效基团的选择性增强元件的效果被证明是相加的，并且导致化合物对 TbNMT 的选择性比 HsNMT 的选择性高 1000 倍。对该混合系列的进一步优化已鉴定出具有显着杀锥虫活性、能够穿过血脑屏障的化合物。通过使用 CF-1 mdr1a 缺陷小鼠，我们能够在 2 期非洲昏睡病小鼠模型中证明体内完全治愈。这项工作和之前的工作为 NMT 作为人类非洲锥虫病外周和中枢神经系统疾病阶段的药物靶点提供了非常有力的验证。
Crystallography has guided the hybridization of two series of Trypanosoma bruceiN-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood–brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
Brand, Stephen;Cleghorn, Laura A. T.;McElroy, Stuart P.;Robinson, David A.;Smith, Victoria C.;Hallyburton, Irene;Harrison, Justin R.;Norcross, Neil R.;Spinks, Daniel;Bayliss, Tracy;Norval, Suzanne;Stojanovski, Laste;Torrie, Leah S.;Frearson, Julie A.;Brenk, Ruth;Fairlamb, Alan H.;Ferguson, Michael A. J.;Read, Kevin D.;Wyatt, Paul G.;Gilbert, Ian H.
通讯作者：
Gilbert, Ian H.
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
影响因子：
7.3
作者：
Jamieson, Craig;Moir, Elizabeth M.;Wishart, Grant
通讯作者：
Wishart, Grant