Structure-guided redesign of an antischistosomal drug

 描述（由申请人提供）：抗血吸虫药物的结构导向再设计治疗血吸虫病（由血吸虫曼氏血吸虫（Sm）、血吸虫（Sh）和日本血吸虫（Sj）引起的疾病）的新药是迫切需要的，因为仅使用单一疗法（吡喹酮- PZQ）治疗，并且没有有效的疫苗。奥曲喹（OXA）具有良好的安全记录，对Sm非常有效，但不再使用，因为与PZQ不同，OXA对Sh和Sj无效。海波龙是一种与OXA相关的药物，对Sm和Sh有活性，对Sj无活性，但其不利的肝毒性特征排除了作为治疗剂的用途。OXA和HC是前体药物，可被溶酶体酶激活。我们最近确定了OXA激活酶在Sm作为磺基转移酶（SmSULT），我们还确定了它的同系物在SH（ShSULT）和Sj（SjSULT）。我们的SmSULT* 辅因子 *OXA复合物的1.75 μ m晶体结构揭示了Sm中OXA活化和药物作用的分子基础。ShSULT和SjSULT酶分别与SmSULT共享71%和58%的序列同一性。在Sm-、Sh-和SjSULT之间观察到的高度序列和结构相似性表明这些结构可用作设计将杀死Sm、Sh和Sj的修饰的OXA衍生物的模板。用于实现这一目标的方法包括（i）酶 * 辅因子 *OXA复合物的比较结构和生化分析，（ii）负责物种特异性药物作用的关键氨基酸的实验测定，以及（iii）结构指导设计的迭代循环与药物活化和寄生虫杀灭的体外研究配对，随后合成新的OXA衍生物/类似物，并在感染的啮齿动物中进行最终测试。泛特异性OXA衍生物将提供PZQ的替代物用于抗肿瘤治疗，或PZQ的伴侣以延缓耐药性的演变并使化疗更有效。

 DESCRIPTION (provided by applicant): Structure-guided redesign of an antischistosomal drug New drugs to treat schistosomiasis, a disease caused by the blood flukes Schistosoma mansoni (Sm), Schistosoma haemtobium (Sh) and Schistosoma japonicum (Sj), are urgently needed because only treatment with a monotherapy (Praziquantel - PZQ) is used and effective vaccines are not available. Oxamniquine (OXA) has an excellent safety record and it is extremely effective against Sm, but it is no longer used because unlike PZQ, OXA is ineffective against Sh and Sj. Hycanthone, a drug related to OXA, is active against Sm and Sh and inactive against Sj, but its unfavorable hepatotoxicity profile precludes use as a therapeutic agent. OXA and HC are pro-drugs that become activated by a schistosome enzyme. We recently identified the OXA-activating enzyme in Sm as a sulfotransferase (SmSULT) and we also identified its homologs in Sh (ShSULT) and Sj (SjSULT). Our 1.75 Å crystal structure of the SmSULT*cofactor*OXA complex reveals the molecular basis for OXA activation and drug action in Sm. ShSULT and SjSULT enzymes share 71% and 58% sequence identity with SmSULT, respectively. The high degree of sequence and structural similarity observed between Sm-, Sh- and SjSULT suggests these structures can be used as templates in the design of modified OXA-derivatives that will kill Sm, Sh, and Sj. The methods used to achieve this goal include (i) comparative structural and biochemical analyses of enzyme*cofactor*OXA complexes, (ii) experimental determination of the critical amino acids responsible for species-specific drug action, and (iii) iterative cycles of structure-guided design paired with in vitro studies of drug activation and parasite killing, followed by syntheses of novel OXA derivatives/analogs with final testing in infected rodents. A pan-specific OXA derivative would provide an alternative to PZQ for schistosome treatment, or a partner for PZQ to retard the evolution of resistance and make chemotherapy more effective.