Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery
Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery
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DOI：
10.1371/journal.pntd.0006301
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发表时间：
2018-02-01
影响因子：
3.8
通讯作者：
Zikova, Alena
中科院分区：
文献类型：
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作者：
Dolezelova, Eva;Teran, David;Zikova, Alena
由于毒性和依从性问题，以及对现有药物出现抗药性，需要治疗人类非洲锥虫病的新药。开发新型抗锥虫药物的一个潜在途径是通过抑制6-氧嘌呤挽救途径来合成DNA/RNA生产所需的核苷一磷酸。这是鉴于这样一个事实，即锥虫缺乏从头合成嘌呤环的机制。为了验证这种方法作为药物靶点的有效性，我们已经在布鲁氏锥虫感染阶段对三种6-氧嘌呤磷酸核糖转移酶(PRTase)亚型进行了沉默，表明这些酶的联合活性对寄生虫的生存至关重要。此外，我们还确定了其中两种异构体与几种无环核苷膦(ANPs)的络合物的晶体结构，ANPs是一类先前被证明对包括恶性疟原虫在内的几个物种的6-氧嘌呤PRTase具有抑制作用的化合物。其中最有效的化合物的K-I值低至60 nM，细胞检测的IC50值低至4微米。这一数据为进一步研究该途径作为抗锥虫药物发现的靶点提供了坚实的平台。
Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites' viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6-oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have K-i values as low as 60 nM, and IC50 values in cell based assays as low as 4 mu M. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery.