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Chemical Interrogation of Human DNA Cytosine Deaminases

人类 DNA 胞嘧啶脱氨酶的化学研究

基本信息

批准号：
9275136
负责人：
Daniel A Harki
金额：
$ 8.7万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275136
关键词：
APOCEC3G gene Active Sites Binding Sites Biochemical Biochemistry Biological Assay Biology Catalysis Cell Culture Techniques Cells Chemicals Clinical Communicable Diseases Complementary DNA Computer Simulation Crystallography Cysteine Cytosine Cytosine deaminase DNA DNA Binding Data Deaminase Development Drug Design Drug resistance Enzymes Evolution Family Family member Foundations Future Genetic Genets Genome Genomics Goals Growth HIV HIV-1 Health Heterogeneity Human Immune Individual Knowledge Lead Life Malignant Neoplasms Methods Modification Mutation Natural Immunity Nature Nuclear Outcome Patients Pharmaceutical Chemistry Pharmaceutical Preparations Play Proteins Publishing Reporting Research Role Scientist Solvents Source Sulfhydryl Compounds Testing Therapeutic Uracil Viral Work Zinc analog base cancer genome chemical synthesis combat computational chemistry design drug development drug discovery high throughput screening human DNA human disease inhibitor/antagonist innovation meetings novel novel therapeutics overexpression scaffold small molecule small molecule inhibitor tumor

项目摘要

DESCRIPTION (provided by applicant): APOBEC3 (A3) enzymes are DNA cytosine-to-uracil deaminases that target foreign DNA for destruction as part of innate immunity. A3 enzymes also play integral roles in multiple human diseases. APOBEC3G (A3G) sub-lethally deaminates HIV-1 cDNA during replication, providing a source of genomic mutation that contributes to viral evolution, adaptation, and drug resistance. APOBEC3B (A3B) is overexpressed in at least 6 human cancers, resulting in high levels of C-to-U genomic mutations that drive tumor evolution, heterogeneity, and drug resistance. Therefore, small molecule inhibitors of A3G and A3B may ultimately yield novel therapeutics for applications in infectious disease and cancer. The long-term goal of this project is to develop small molecule inhibitors of A3G and A3B as clinical drugs. The objective in this application is to develop potent chemical probes of A3G and A3B to enable mechanistic studies of both enzymes. High-throughput screening, chemical synthesis, and biochemical testing have been previously employed to identify covalent inhibitors of A3G. The central hypotheses of this application are: 1) Recently published A3G covalent inhibitors have identified a region of the enzyme that is susceptible to small molecule modulation, which can be exploited in probe design, and 2) Recently identified and unpublished non-covalent inhibitors of A3G and A3B can be optimized by computation-based methods to yield potent and selective chemical probes. The rationale for developing A3G and A3B small molecule probes is to enable mechanistic studies of their roles in HIV-1 restriction and cancer evolution, respectively. Furthermore, small molecule A3G and A3B probes will serve as launch points for future drug discovery efforts. The specific aims of this application are: 1) To develop bifunctiona and reversible covalent A3G inhibitors and 2) To develop non-covalent inhibitors of A3G and A3B. In the first aim, existing small molecules that covalently target A3G will be structurally modified to also engage the zinc atom of A3G, yielding bifunctional inhibitors that are predicted to be more potent than existing compounds. Additionally, existing covalent inhibitors of A3G will be modified to incorporate chemical moieties that can reversibly engage A3G Cys321, yielding molecules that are predicted to be less cross-reactive than the established covalent inhibitors, and therefore, will inhibit A3G in cell lysate and cells. In the second aim, computational modeling based on unpublished non-covalent A3G and A3B inhibitors will be used to guide the development of more selective and more potent non-covalent inhibitors of A3G and A3B. This approach is innovative because the small molecule inhibitors of A3G and A3B described in this proposal represent the first- in-class molecules known to target these enzymes. This work is also innovative due to the unique cross- disciplinary team of scientists, all with expertise in mutation research, that are focused on delivering novel chemical probes of A3 deaminases. The proposed research is significant because it expected to deliver fundamental chemical knowledge of A3 inhibition that will serve as the underpinning for future drugs.