Structure-guided redesign of an antischistosomal drug

 描述(申请人提供)：抗血吸虫药物的结构指导重新设计治疗血吸虫病的新药，这是一种由血吸虫引起的疾病，由于只使用单一疗法(吡喹酮-PZQ)治疗，因此迫切需要这种疾病。奥沙米昆(Oxamniquine，OXA)有很好的安全记录，对Sm非常有效，但它不再被使用，因为与PZQ不同，OXA对Sh和Sj无效。氢坎酮是一种与OXA相关的药物，对Sm和Sh有活性，对Sj没有活性，但其不利的肝毒性特征排除了用作治疗剂的可能性。OXA和HC是被血吸虫酶激活的前体药物。我们最近鉴定了Sm中的OXA激活酶为磺基转移酶(SmSULT)，并鉴定了它在Sh(ShSULT)和Sj(SjSULT)中的同源物。我们的SmSULT*辅因子*OXA复合体的1.75？晶体结构揭示了Sm中OXA激活和药物作用的分子基础。ShSULT和SjSULT酶与SmSULT的序列同源性分别为71%和58%。观察到Sm-、Sh-和SjSULT之间高度的序列和结构相似性，表明这些结构可以用作设计将杀死Sm、Sh和Sj的修饰OXA-衍生物的模板。实现这一目标的方法包括(I)酶*辅因子*OXA复合体的比较结构和生化分析，(Ii)对负责特定物种药物作用的关键氨基酸的实验确定，以及(Iii)结构指导设计与药物激活和寄生虫杀灭的体外研究相结合的迭代循环，然后合成新的OXA衍生物/类似物，并在受感染的啮齿动物上进行最终测试。泛特异性OXA衍生物将为血吸虫治疗提供PZQ的替代方案，或者PZQ的合作伙伴，以延缓耐药性的演变，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.