Structure-guided redesign of an antischistosomal drug

抗血吸虫药物的结构引导重新设计

基本信息

批准号：
9094447
负责人：
Peter JOHN HART
金额：
$ 51.56万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-24 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9094447
关键词：
Affect Africa Amino Acids Asia Binding Biochemical Biological Assay Chemicals Coenzymes Complex Data Development Disease Drug effect disorder Enzyme Interaction Enzymes Evolution Family Genes Goals Health Hepatotoxicity Homologous Gene Homology Modeling Human In Vitro Measures Methods Middle East Modification Molecular Mutation Parasite resistance Parasites Pharmaceutical Preparations Post-Translational Protein Processing Praziquantel Prodrugs Property Proteins Resistance Resolution Safety Schistosoma Schistosoma japonicum Schistosoma mansoni Schistosomatidae Schistosome Parasite Schistosomiasis Site-Directed Mutagenesis South America Structure Testing Therapeutic Agents Vaccines Variant West Indies Work analog base cell motility chemotherapy cofactor comparative design improved infected vector rodent killings novel novel therapeutics research study scale up sulfotransferase

项目摘要

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.

DESCRIPTION (provided by application): 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）具有出色的安全记录，并且对SM非常有效，但不再使用它，因为与PZQ不同，OXA对SH和SJ无效。与OXA有关的药物Hycanthone对SM和SH具有活性，并且对SJ不活跃，但其不利的肝毒性概况排除了作为治疗剂的使用。 OXA和HC是促毒物，由血吸虫酶激活。我们最近将SM中的OXA激活酶确定为硫代转移酶（SMSULT），我们还确定了其在SH（SHSULT）和SJ（SJSULT）中的同源物。我们的Smsult*cofactor*OXA复合物的1.75Å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酶分别与SMSULT共享71％和58％的序列身份。在SM，SH-和SJSULT之间观察到的高度序列和结构相似性表明，这些结构可以用作修饰的Oxa衍生物设计的模板，这些模板将杀死SM，SH和SJ。用于实现此目标的方法包括（i）酶*cofactor*oxa复合物的比较结构和生化分析，（ii）对负责特异性药物作用的关键氨基酸的实验确定，以及（iii）迭代循环的结构指导设计与与药物激活的牛仔构成相似的牛仔构成的研究，其合成和副层杀伤的牛仔素，受感染啮齿动物的最终测试。 PAN特异性的OXA衍生物将为PZQ提供螺旋体治疗的替代方案，或者是PZQ的伴侣，以阻止耐药性的演变并使化学疗法更有效。