Developing Therapeutics against Giardia and Other Anaerobic Protozoa by Targeting Parasite Fatty Acyl-CoA Synthetase (ACS)

通过靶向寄生虫脂肪酰辅酶 A 合成酶 (ACS) 开发针对贾第鞭毛虫和其他厌氧原生动物的治疗方法

• 批准号: 9099754
• 负责人: GUAN ZHU
• 金额: $ 19.9万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-26 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099754
• 关键词: Acanthamoeba; Accounting; Acyl Coenzyme A; Animal Model; Biochemical; Biochemistry; Biological Assay; Cessation of life; Coenzyme A Ligases; Coupled; Cryptosporidium; Cryptosporidium parvum; Data; Disease; Drug Targeting; Drug effect disorder; Drug resistance; Entamoeba; Entamoeba histolytica; Enzymes; Evaluation; Exhibits; FDA approved; Fatty Acids; Genes; Genome; Giardia; Giardia lamblia; Growth; Health; In Vitro; Libraries; Lipids; Membrane; Metabolic Pathway; Modeling; Molecular; Parasites; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Protein Isoforms; Protozoa; Reporting; Research; Sexually Transmitted Diseases; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Trichomonas; Trichomonas vaginalis; analog; data mining; drug structure; drug testing; efficacy testing; enzyme activity; fatty acid elongases; fatty acid metabolism; fatty acid transport; functional genomics; genome sequencing; high throughput screening; in vivo; inhibitor/antagonist; new therapeutic target; novel; novel therapeutics; oxidation; screening; triacsin C

 DESCRIPTION (provided by applicant): Fatty acids (FAs) are activated by fatty acyl-CoA synthetase (ACS) before they enter subsequent metabolic pathways. The anaerobic protozoa Giardia, Entamoeba and Trichomonas are unable to synthesize FAs de novo. They scavenge FAs from the host and/or microenvironment, but possess ACS for FA activation and FA elongase (ELO) for limited FA extension. We discovered that the ACS inhibitor triacsin C (triaC) could inhibit the ACS enzyme activity in Giardia as well as the parasite growth in vitro, indicatin that ACSs could serve as novel drug targets. In this project, we will fully explore the potential t develop novel therapeutics against Giardia and other anaerobic protozoa by targeting parasite ACS enzymes and achieving the following aims. In the R21 phase, we will: 1) determine the biochemical features of GiACS enzymes and develop a high- throughput screening (HTS) assay to test FDA-approved drugs; 2) synthesize analogs of triaC for testing anti-GiACS efficacy and SAR analysis; 3) test the efficacy of triaC and top hits against strains from three Giardia assemblages; and 4) assess whether ACS could serve as a broad-spectrum drug target by testing the efficacy of triaC and top screening hits against other anaerobic protozoa, including Acanthamoeba, Entamoeba and Trichomonas. In the R33 phase, we will: 1) discover novel anti-GiACS inhibitors by HTS of the ActiProbe10K library; 2) synthesize more triaC analogs and analogs of top hits for testing efficacy against Giardia and other protozoa in vitro and SAR analysis, and validate the mechanism of drug action by functional genomics analysis in Giardia; 3) characterize ACSs from other protozoa that are sensitive to the inhibition of ACS for screening known drugs and SAR analysis; and 4) evaluate top hits in in vitro and in vivo pre-efficacy ADME assays and for efficacy against Giardia in an animal model. We have recently reported that ACS could serve as a novel drug target in Cryptosporidium. Our preliminary data also confirmed the efficacy of triaC on Giardia and Acanthamoeba, which strongly supports ACS as a broad-spectrum drug target in protozoan parasites. By taking advantage of our team's expertise in parasite biochemistry and medicinal chemistry, the successful completion of this project is expected with a great potential to identify a number of known drugs and novel compounds efficacious against Giardia and other anaerobic protozoa for repurposing and/or for developing new therapeutics.

 描述（由申请人提供）：脂肪酸（FA）在进入后续代谢途径之前被脂肪酰辅酶A合成酶（ACS）激活。厌氧原生动物贾第鞭毛虫、内阿米巴和毛滴虫无法从头合成FA，它们从头开始清除FA。宿主和/或微环境，但具有用于 FA 激活的 ACS 和用于有限 FA 延伸的 FA 延长酶 (ELO)。发现ACS抑制剂三嗪C（triaC）可以抑制贾第鞭毛虫体内的ACS酶活性以及体外寄生虫的生长，表明ACS可以作为新的药物靶标。在这个项目中，我们将充分探索开发新药物的潜力。通过靶向寄生虫 ACS 酶来治疗贾第鞭毛虫和其他厌氧原生动物并实现以下目标 在 R21 阶段，我们将： 1）确定 GiACS 酶的生化特征。并开发高通量筛选 (HTS) 测定法来测试 FDA 批准的药物；2) 合成 triaC 类似物，用于测试抗 GiACS 功效和 SAR 分析；3) 测试 triaC 和热门产品对三种贾第鞭毛虫组合菌株的功效； ；4) 通过测试 triaC 和顶级筛选药物对其他厌氧原生动物（包括棘阿米巴）的功效，评估 ACS 是否可以作为广谱药物靶点，在 R33 阶段，我们将：1）通过 ActiProbe10K 库的 HTS 发现新型抗 GiACS 抑制剂；2）合成更多 triaC 类似物和热门类似物，用于测试对贾第鞭毛虫和其他原生动物的体外功效和 SAR。分析，并通过贾第鞭毛虫的功能基因组学分析验证药物作用机制；3) 表征对抑制敏感的其他原生动物的 ACS； ACS 筛选已知药物和 SAR 分析；4) 评估体外和体内药效前 ADME 测定中的热门药物以及动物模型中针对贾第鞭毛虫的功效。我们的初步数据还证实了 triaC 对贾第鞭毛虫和棘阿米巴的功效，这有力地支持了 ACS 作为原生动物寄生虫的广谱药物靶点。凭借团队在寄生虫生物化学和药物化学方面的专业知识，预计该项目的成功完成将具有巨大的潜力，以确定许多对贾第鞭毛虫和其他厌氧原生动物有效的已知药物和新型化合物，以重新利用和/或开发新疗法。