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 迫切需要治疗血吸虫病的新药，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，因为仅使用单一疗法（吡喹酮 - PZQ）进行治疗，并且没有有效的疫苗。奥沙尼喹 (OXA) 具有良好的安全性记录，对 Sm 极其有效，但已不再使用，因为与 PZQ 不同，OXA 对 Sh 无效，而与 OXA 相关的药物 Sj 对 Sm 和 Sh 具有活性。 OXA 和 HC 是被血吸虫激活的前药，但其不利的肝毒性使其不能用作治疗剂。我们最近鉴定出 Sm 中的 OXA 激活酶为磺基转移酶 (SmSULT)，并且我们还在 Sh (ShSULT) 和 Sj (SjSULT) 中鉴定出其同系物。我们的 SmSULT*辅因子*OXA 复合物的 1.75 Å 晶体结构揭示了该酶。 Sm 中 OXA 激活和药物作用的分子基础与 Sm 具有 71% 和 58% 的序列同一性。 SmSULT 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，从而杀死 Sm、Sh 和 Sj。目标包括 (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) 迭代循环结构引导设计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，并在受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 的替代品用于血吸虫治疗。 PZQ 的合作伙伴可以延缓耐药性的演变并使化疗更加有效。