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.

利什曼尼亚（Leishmania）和其他动力质体寄生虫会引起毁灭性疾病，遭受数百万人的困扰，而多诺瓦尼（L. donovani）通常会引起致命的内脏利什曼病。由于当前的药物方案严重不足，因此必须确定可以利用的特定靶标，这些靶标可以开发新的口服生物利用药物，以改善治疗选择。这些寄生虫中的Neddylation途径代表了一个很高的机会靶标的，其多种酶可能对于细胞内疾病的寄生虫生存至关重要。该途径使用特定的E1，E2和E3激活酶将小的泛素样蛋白NEDD8连接到各种细胞底物上，例如Cullin rigase，它们是必需泛素化途径的重要组成部分。这些底物的Neddylation通常会激活其功能，从而调节相关的下游途径。值得注意的是，已经将3种NEDDYDYLATY酶的每种酶用于人类的抗癌药物，其中一种实验性药物正在接受3期临床试验。这些成功表明，每种酶都是可药物的，并且对与多诺瓦氏乳杆菌的直系同源但高度序列的分歧酶的平行研究很可能鉴定出寄生虫特异性药物（例如抑制剂），这些抑制剂将使寄生虫具有致命作用，但对寄生虫的影响很小，但对宿主细胞的影响很小。该项目的目的是在donovani中删除这些酶的三个基因中的每个基因，称为UBA3，DCN1和CSN5，并确定此类缺失是否会严重损害寄生虫生命周期中引起细胞内疾病的阶段的生长。成功地证明了某些或全部这些NEDDYLATY酶的必要性，将验证它们作为药物靶标，其寄生虫选择性小分子的抑制作用将为这种繁重的全球感染性疾病提供新颖的治疗方式。这些结果将为随后的药物开发计划提供动力，以针对该途径。此外，对无效突变体的表型研究将揭示受Neddylation途径控制的重要生物学过程，因此将为这种病原体的基本生物学提供强大的见解。