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 μM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery.

由于毒性和合规性问题以及对当前药物的抗药性的出现，需要用于治疗人类非洲锥虫病的新药物。开发新型抗锥虫药物的潜在方法是抑制6-氧代嘌呤的挽救途径，该途径合成了DNA / RNA生产所需的核苷单磷酸。鉴于锥虫体缺乏嘌呤环从头合成的机制。为了验证该方法是否可作为药物靶标，我们已将布鲁氏锥虫感染阶段的三个6-氧代嘌呤磷酸核糖基转移酶（PRTase）亚型沉默了。表明这些酶的联合活性对于寄生虫的生存能力至关重要。此外，我们已经确定了与两个无环核苷膦酸酯（ANP）配合形成的这些同工型中的两个的晶体结构，该化合物先前已显示出抑制多种恶性疟原虫等物种的6-氧嘌呤PRTase的作用。这些化合物中最有效的K _i值低至60 nM，而基于细胞的测定中的IC ₅₀值低至4μM。该数据为进一步研究将该途径用作抗锥虫药物发现的靶标提供了坚实的平台。