BIOCHEMISTRY OF TRYPANOSOMATIDS--BASIS FOR DRUG DESIGN

利用锥虫作为模式寄生虫，我们已经定义了一种生化 宿主和寄生虫之间的差异，这是理想的选择， 新的杀锥虫剂的设计 这种差异的基础在于 在锥虫对氧化应激的敏感性方面， 宿主有足够的、多种防御机制。 在当前 应用，我们建议深入研究两个方面。 这些包括 在体内锥虫中产生氧自由基的方法和 降低锥虫耐受内源性或外源性毒素的能力的方法 外源性氧化应激通过干扰维持减少 谷胱甘肽 初步证据表明， 醌类产生超氧化物和过氧化氢， 体外锥虫。 许多这些新的代理商是溶解在 微摩尔范围;然而，只有一个显示出任何杀锥虫活性 in vivo. 体内缺乏活性，反映了快速清除和 哺乳动物宿主的新陈代谢。 醌类似乎很容易反应， 迈克尔除了蛋白质和被灭活。 一个特工，2，3 双-（脒基腙丁基）-1，4萘醌，保留部分 体内生物活性表明， 可避免哺乳动物宿主代谢同时保留 杀锥虫活性。 本文介绍了几种合成方法的原理和合成路线， 这些新的衍生物的描述。 第二个攻击点是 评价的是谷胱甘肽还原酶。 这种酶 负责还原型谷胱甘肽从氧化型谷胱甘肽 谷胱甘肽以前没有从锥虫中分离出来。 是 建议将这种酶分离，表征并与 哺乳动物酶 此外，合成了一些新的药剂 可以与酶的活性位点相互作用， 进行。 重点将放在寻找类似物， 有利于在锥虫的活性部位反应 酶比哺乳动物的酶。 希望这些研究能够 鉴定一种含有非金属的化合物， 二硫醇受体，其将取代氧化砷的砷部分。

Utilizing trypanosomes as a model parasite, we have defined a biochemical difference between the host and the parasite which is ideal as a choice for the design of new trypanocidal agents. The basis of this difference lies in the sensitivity of trypanosomes to oxidant stress while the mammalian host has adequate and multiple defense mechanisms. In the current application, we propose to study two aspects in depth. These include a means of generating oxygen free radicals in the trypanosome in vivo and a way of decreasing the ability of the trypanosome to withstand indogenous or exogenous oxidant stress by interferring with the maintenance of reduced glutathione. Preliminary evidence points to the ability of a number of quinones to generate superoxide and hydrogen peroxide which can lyse trypanosomes in vitro. Many of these new agents are lytic in the micromolar range; however, only one has displayed any trypanocidal activity in vivo. The lack of activity in vivo, reflects the rapid clearance and metabolism by the mammalian host. Quinones appear to readily react by Michael addition to proteins and be inactivated. The one agent, 2,3 bis-(guanylhydrozone butyl)-1,4 naphthoquinone that retained partial biological activity in vivo points to the possibility of designing new agents which can avoid metabolism by the mammalian host while retaining trypanocidal activity. The rationale and the synthetic routes for a number of these new derivatives are described. The second point of attack to be evaluated is the enzyme glutathione reductase. This enzyme which is responsible for the regeneration of reduced glutathione from oxidized glutathione has not previously been isolated from trypanosomes. It is proposed that this enzyme be isolated, characterized and compared with the mammalian enzyme. In addition, the synthesis of the number of new agents which could interact with the active site of the enzyme will be undertaken. Emphasis will be placed on finding analogs which are more favorably positioned for reaction in the active site of the trypanosome enzyme than in the mammalian enzyme. These studies, hopefully, will lead to the identification of a compound which will contain a nonmetalic di-thiol acceptor which will replace the arsenic moiety of molarsenoxide.