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The Neddylation Pathway in Leishmania donovani - A High Opportunity Target

杜氏利什曼原虫的 Neddylation 途径 - 高机会目标

基本信息

批准号：
10349372
负责人：
Scott M Landfear
金额：
$ 23.1万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349372
关键词：
Address Antineoplastic Agents Bioavailable Biochemical Biological Biological Process Biology COPS5 gene Cell Cycle Progression Cells Cessation of life Chemicals Cleaved cell Collaborations Communicable Diseases Cullin Proteins Cutaneous Development Disease Drug Targeting Ensure Enzymes Eukaryota Future Generations Genes Growth Hand Human Impairment Inbred BALB C Mice Individual Infection Investigation Kentucky Knock-out Leishmania Leishmania donovani Life Cycle Stages Ligase Link Lysine Malaria Malignant Neoplasms Measurement Modality Molecular Genetics Monitor Mus Nature Oral Parasites Parasitic infection Pathway interactions Pharmaceutical Preparations Phase III Clinical Trials Phenotype Positioning Attribute Post-Translational Protein Processing Program Development Property Protein Biochemistry Proteins Regimen Role Saint Jude Children&apos s Research Hospital Subcellular structure Testing Therapeutic Time Ubiquitin Like Proteins Ubiquitination Universities Validation Visceral Leishmaniasis X-Ray Crystallography amino group base conditional knockout drug candidate drug development improved inhibitor/antagonist insight interest knockout gene mutant novel novel therapeutics pathogen small molecule success

项目摘要

Leishmania and other kinetoplastid parasites cause devastating diseases that afflict millions of people, and L. donovani typically causes fatal visceral leishmaniasis. Because current drug regimens are woefully inadequate, it is important to identify specific targets that can be exploited for development of novel orally bioavailable drugs that will improve therapeutic options. The neddylation pathway in these parasites represents a high opportunity target with multiple enzymes that are likely essential for survival of intracellular disease-causing parasites. This pathway uses specific E1, E2, and E3 activating enzymes to attach the small ubiquitin -like protein, NEDD8, onto various cellular substrates, such as the cullin ligases that are important components of the essential ubiquitination pathway. Neddylation of these substrates typically activates their functions and thus regulates the relevant downstream pathway. Significantly, each of 3 neddylation enzymes has already been targeted for development of anti-cancer drugs in humans, with one experimental drug undergoing phase 3 clinical trials. These successes indicate that each enzyme is druggable and that parallel studies on the orthologous but highly sequence divergent enzymes from L. donovani is likely to identify parasite-specific drug- like inhibitors that will inactivate the neddylation pathway with lethal effects for the parasite but with minimal effects on host cells. The purpose of this project is to delete in L. donovani each of the 3 genes for these enzymes, called UBA3, DCN1, and CSN5, and determine whether such deletions strongly impair growth of the intracellular disease-causing stage of the parasite life cycle. Successful demonstration of essentiality for some or all of these neddylation enzymes will validate them as drug targets whose inhibition by parasite-selective small molecules would provide novel therapeutic modalities for this burdensome global infectious disease. These results will provide the impetus for a subsequent drug development program to target this pathway. In addition, phenotypic studies on the null mutants will reveal important biological processes governed by the neddylation pathway and will thus provide powerful insights into the basic biology of this pathogen.

利什曼原虫和其他动质体寄生虫导致毁灭性的疾病，折磨数百万人，和L。donovani通常会导致致命的内脏利什曼病。由于目前的药物治疗方案严重不足，因此确定可用于开发新型口服生物可利用药物的特定靶点非常重要，这些药物将改善治疗选择。这些寄生虫中的neddylation途径代表了具有多种酶的高机会靶点，这些酶可能是细胞内致病寄生虫生存所必需的。该途径使用特异性E1、E2和E3活化酶将小泛素样蛋白NEDD 8附着到各种细胞底物上，例如作为必需泛素化途径的重要组分的cullin连接酶。这些底物的Neddylation通常激活它们的功能，从而调节相关的下游途径。值得注意的是，3种neddylation酶中的每一种都已经成为人类抗癌药物开发的目标，其中一种实验药物正在进行3期临床试验。这些成功表明，每种酶都是可药用的，对来自L。多诺万尼可能会发现寄生虫特异性药物样抑制剂，这些抑制剂将灭活奈迪化途径，对寄生虫产生致命影响，但对宿主细胞的影响最小。这个项目的目的是删除在L。donovani的每3个基因的这些酶，称为UBA 3，DCN 1和CSN 5，并确定是否这样的删除强烈损害的细胞内致病阶段的寄生虫生命周期的增长。成功证明这些neddylation酶中的一些或全部的必要性将验证它们作为药物靶标，其通过寄生虫选择性小分子的抑制将为这种负担沉重的全球传染病提供新的治疗方式。这些结果将为后续针对这一途径的药物开发计划提供动力。此外，对无效突变体的表型研究将揭示由neddylation途径控制的重要生物学过程，从而为这种病原体的基础生物学提供强有力的见解。