Improving CPT-11 Efficacy Using Structural and Chemical Biology

利用结构生物学和化学生物学提高 CPT-11 功效

基本信息

批准号：
9128581
负责人：
Matthew R Redinbo
金额：
$ 26.39万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-23 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128581
关键词：
Acute Address Adverse effects Animals Anti-Inflammatory Agents Anti-inflammatory Antineoplastic Agents Applied Research Bacteria Basic Science Beta-glucuronidase Binding Biological Biology Camptothecin-11 Cell Death Chemicals Chemotherapy-Oncologic Procedure Colorectal Cancer Diarrhea Dose-Limiting Enteral Enzymes Epithelial Cells Glucuronic Acids Glucuronidase Inhibitor Goals Health Human In Vitro Intestines Knowledge Life Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Metagenomics Molecular Oral Pharmaceutical Chemistry Pharmaceutical Preparations Proteins Reagent Research Science Structural Biochemistry Structure Symbiosis Testing Therapeutic Time Toxic effect Ulcer deep sequencing design enzyme activity gut microbiome gut microbiota improved improved outcome inhibitor/antagonist irinotecan killings microbial microbiome microbiota mouse model mutualism novel novel therapeutics structural biology sugar therapeutic enzyme tool

项目摘要

DESCRIPTION (provided by applicant): We are alleviating the toxicity of the anticancer drug CPT-11 by modulating components of the GI microbiome. CPT-11 is essential in treating colorectal and pancreatic cancer, but dose-limiting toxicity severely reduces its efficacy. This toxicity is caused by a bacterial enzyme in enteric microbial symbiotes. The enzyme, ß-glucuronidase, removes the inactivating glucuronic acid sugar from CPT-11's key metabolite, which reactivates the drug in the GI and produces epithelial cell death and acute diarrhea. We hypothesized that the selective, non-lethal inhibition of microbial ß-glucuronidases would alleviate this side effect. This hypothesis tested true in proof-of-concept molecular-to-animal studies conducted in the previous project period. We will now advance the project in three crucial ways. First, we will characterize the range of active ß-glucuronidases present in the GI microbiome using structural biology and biochemistry. Second, we will create differentially optimized bacterial ß-glucuronidase inhibitors via structural and chemical biology. Third, using deep-sequencing and metagenomics, we will unravel how this approach impacts the composition and activity of the GI microbiome. In summary, we seek to advance a novel paradigm - inhibiting specific microbial enzymes for therapeutic gain without harming the bacterial symbiotes essential for human health.

描述（由应用提供）：我们通过调节胃肠道微生物组的成分来减轻抗癌药物CPT-11的毒性。 CPT-11对于治疗结直肠癌和胰腺癌至关重要，但是限制剂量的毒性严重降低了其有效性。这种毒性是由促进微生物符号中的细菌酶引起的。酶，β-葡萄糖醛酸酶，从CPT-11的关键代谢产物中去除失活的谷氨酸糖，该代谢物在GI中重新激活该药物并产生上皮细胞死亡和急性腹泻。我们假设选择性，非致命抑制微生物β-葡萄糖醛酸苷酶会减轻这种副作用。该假设在上一个项目期间进行的概念验证验证验证分子到动物研究中进行了正确检验。现在，我们将以三种至关重要的方式推进该项目。首先，我们将使用结构生物学和生物化学来表征GI微生物组中存在的活性β-葡萄糖醛酸苷酶的范围。其次，我们将通过结构和化学生物学创建差异优化的细菌β-葡萄糖醛酸苷酶抑制剂。第三，使用深层序列和宏基因组学，我们将阐明这种方法如何影响GI微生物组的组成和活性。总而言之，我们试图推进一种新型的范式 - 抑制特定的微生物酶，以促进治疗性增长，而不会损害对人类健康必不可少的细菌共生。