Structure-guided redesign of an antischistosomal drug

抗血吸虫药物的结构引导重新设计

• 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
• 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

 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.

 描述（由申请人提供）：抗血吸虫药物的结构引导重新设计 血吸虫病是一种由曼氏血吸虫（Sm）、埃及血吸虫（Sh）和日本血吸虫（Sj）血吸虫引起的疾病，由于仅采用单一疗法（吡喹酮 - PZQ）治疗且没有有效的疫苗，因此迫切需要治疗血吸虫病的新药。奥沙尼喹 (OXA) 具有出色的安全性记录，并且对 Sm 极其有效，但已不再使用，因为与 PZQ 不同，OXA 对 Sh 和 Sj 无效。 Hycanthone 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使其不能用作治疗剂。 OXA 和 HC 是被血吸虫酶激活的前药。我们最近将 Sm 中的 OXA 激活酶鉴定为磺基转移酶 (SmSULT)，并且我们还在 Sh (ShSULT) 和 Sj (SjSULT) 中鉴定了其同系物。我们的 SmSULT*辅因子*OXA 复合物的 1.75 Å 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 具有 71% 和 58% 的序列同一性。 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设计修饰的OXA-衍生物的模板，该衍生物将杀死Sm、Sh和Sj。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）实验确定负责物种特异性药物作用的关键氨基酸，以及（iii）结构引导设计的迭代循环与药物激活和寄生虫杀灭的体外研究相结合，然后合成新型OXA衍生物/类似物，并最终合成 在受感染的啮齿动物中进行测试。泛特异性 OXA 衍生物将为血吸虫治疗提供 PZQ 的替代品，或者是 PZQ 的伴侣，以延缓耐药性的演变并使化疗更有效。