Targeting isoprenoid biosynthesis for drug discovery: bench to bedside.
Targeting isoprenoid biosynthesis for drug discovery: bench to bedside.
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DOI：
10.1021/ar100026v
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发表时间：
2010-09-21
影响因子：
18.3
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Oldfield, Eric
类异戊二烯的生物合成途径产生了自然界中最大的一类小分子：类异戊二烯(也称为萜类)。因此，毫不奇怪，类异戊二烯生物合成是药物发现的目标，许多药物，如立普妥(用于降低胆固醇)、福善美(用于治疗骨质疏松症)和许多抗感染药物以类异戊二烯生物合成为目标。然而，疟疾、结核病和葡萄球菌感染的耐药性正在上升，被忽视的热带病缺乏廉价有效的药物，抗癌药物的开发进展相对缓慢。因此，类异戊二烯生物合成是一个有吸引力的目标，在这个帐户中，我描述了四个领域的发展，每个领域都使用从一个化学领域获得的知识来指导另一个看似无关的领域的抑制剂(或药物先导)的开发。首先，我描述了IspH酶的机制研究，它存在于疟疾寄生虫和大多数致病细菌中，但不存在于人类中。IspH是一种4Fe异戊二烯4S蛋白，由(E-1-hydroxy-2-methyl-but-2-enyl-4-diphosphate)经2H+/2E−还原(烯丙醇生成烯烃)生成5碳(C5)异戊二烯基二磷酸和二甲基烯丙基二磷酸(−)。其机理是不寻常的，因为它涉及有机金属物种：“金属环”(η2-烯烃)和η1/η3-烯丙基。这些观察结果导致了新型的炔烃抑制剂，这些化合物也形成了金属环。其次，我描述了fpp合酶的结构、功能和抑制作用的研究。fpp合酶是一种以“从头到尾”的方式将ipp和dmapp缩合成倍半萜法尼基二磷酸的大分子。这种酶使用碳阳离子机制，并被骨吸收药物(双膦酸盐)有效地抑制，我证明这种药物也是阻止原生动物体内类固醇生物合成的抗寄生虫剂。此外，除了激活γδT细胞杀死肿瘤细胞外，亲脂性双膦酸盐还可以抑制肿瘤细胞中的蛋白质预烯化和侵袭性，是肿瘤学的重要新线索。第三，我描述了来自金黄色葡萄球菌的一种“头对头”的三萜合成酶--脱氢角鲨烯合成酶的结构和抑制研究。CRTM催化类胡萝卜素毒力因子葡黄素生物合成的第一步：两个FPP分子缩合生成环丙烷(普鲁奎烯二磷酸)。CRTM的结构类似于人类角鲨烯合成酶(SQS)，一些SQS抑制剂(最初作为降胆固醇药物开发)阻止葡萄糖素的生物合成。经过处理的细菌是白色的，没有毒力(因为它们缺乏保护它们免受中性粒细胞产生的活性氧物种的保护的类胡萝卜素屏障)，这使它们容易受到一种新的治疗方法--先天免疫系统清除的影响。最后，我展示了心脏药物胺碘酮，也被认为具有抗真菌活性，在克鲁氏锥虫的氧化奎宁环酶水平上阻止麦角甾醇的生物合成，这项工作导致了它作为一种新型抗寄生虫剂在临床上的使用。在这四个例子中的每一个例子中，我都使用了一个领域(有机金属化学、骨吸收药物、降胆固醇药物、心脏病)的信息来开发一个无关领域的药物线索：一种代表新药搜索的重要进步的“基于知识的”方法。
The isoprenoid biosynthesis pathways produce the largest class of small molecules in Nature: isoprenoids (also called terpenoids). Not surprisingly then, isoprenoid biosynthesis is a target for drug discovery, and many drugssuch as Lipitor (used to lower cholesterol), Fosamax (used to treat osteoporosis), and many anti-infectivestarget isoprenoid biosynthesis. However, drug resistance in malaria, tuberculosis, and staph infections is rising, cheap and effective drugs for the neglected tropical diseases are lacking, and progress in the development of anticancer drugs is relatively slow. Isoprenoid biosynthesis is thus an attractive target, and in this Account, I describe developments in four areas, using in each case knowledge derived from one area of chemistry to guide the development of inhibitors (or drug leads) in another, seemingly unrelated, area.First, I describe mechanistic studies of the enzyme IspH, which is present in malaria parasites and most pathogenic bacteria, but not in humans. IspH is a 4Fe−4S protein and produces the five-carbon (C5) isoprenoids IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) from HMBPP (E-1-hydroxy-2-methyl-but-2-enyl-4-diphosphate) via a 2H+/2e−reduction (of an allyl alcohol to an alkene). The mechanism is unusual in that it involves organometallic species: “metallacycles” (η2-alkenes) and η1/η3-allyls. These observations lead to novel alkyne inhibitors, which also form metallacycles. Second, I describe structure−function−inhibition studies of FPP synthase, the macromolecule that condenses IPP and DMAPP to the sesquiterpene farnesyl diphosphate (FPP) in a “head-to-tail” manner. This enzyme uses a carbocation mechanism and is potently inhibited by bone resorption drugs (bisphosphonates), which I show are also antiparasitic agents that block sterol biosynthesis in protozoa. Moreover, “lipophilic” bisphosphonates inhibit protein prenylation and invasiveness in tumor cells, in addition to activating γδ T-cells to kill tumor cells, and are important new leads in oncology.Third, I describe structural and inhibition studies of a “head-to-head” triterpene synthase, dehydrosqualene synthase (CrtM), fromStaphylococcus aureus. CrtM catalyzes the first committed step in biosynthesis of the carotenoid virulence factor staphyloxanthin: the condensation of two FPP molecules to produce a cyclopropane (presqualene diphosphate). The structure of CrtM is similar to that of human squalene synthase (SQS), and some SQS inhibitors (originally developed as cholesterol-lowering drugs) block staphyloxanthin biosynthesis. Treated bacteria are white and nonvirulent (because they lack the carotenoid shield that protects them from reactive oxygen species produced by neutrophils), rendering them susceptible to innate immune system clearancea new therapeutic approach. And finally, I show that the heart drug amiodarone, also known to have antifungal activity, blocks ergosterol biosynthesis at the level of oxidosqualene cyclase inTrypanosoma cruzi, work that has led to its use in the clinic as a novel antiparasitic agent.In each of these four examples, I use information from one area (organometallic chemistry, bone resorption drugs, cholesterol-lowering agents, heart disease) to develop drug leads in an unrelated area: a “knowledge-based” approach that represents an important advance in the search for new drugs.
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影响因子：
11.2
作者：
Dieli F;Vermijlen D;Fulfaro F;Caccamo N;Meraviglia S;Cicero G;Roberts A;Buccheri S;D'Asaro M;Gebbia N;Salerno A;Eberl M;Hayday AC
通讯作者：
Hayday AC
影响因子：
4.7
作者：
Cromartie, TH;Fisher, KJ;Grossman, JN
通讯作者：
Grossman, JN
影响因子：
6.2
作者：
Luckman, SP;Hughes, DE;Rogers, MJ
通讯作者：
Rogers, MJ
DOI：
10.1124/jpet.300.1.195
发表时间：
2002-01-01
影响因子：
3.5
作者：
Courchesne, WE
通讯作者：
Courchesne, WE
影响因子：
16.6
作者：
Graewert, Tobias;Rohdich, Felix;Groll, Michael
通讯作者：
Groll, Michael