Exploring Post-Type II PKS Frame Modifications

探索 Post-Type II PKS 框架修改

基本信息

批准号：
9110311
负责人：
Jurgen T Rohr
金额：
$ 27.67万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2014-09-10 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9110311
关键词：
Address Anabolism Anthracyclines Antibiotics Antineoplastic Agents Biochemical Biological Catalysis Characteristics Chemicals Chemotherapy-Oncologic Procedure Clinical Collaborations Communicable Diseases Complex Development Drug Interactions Effectiveness Engineering Enzyme Interaction Enzymes Epirubicin Event Evolution Future Generations Goals Health In Vitro Investigation Kentucky Laboratories Lead Malignant Neoplasms Methods Methylation Michigan Modeling Modification Molecular Multienzyme Complexes National Institute of Diabetes and Digestive and Kidney Diseases Natural Product Drug Natural Products Nature Oxidoreductase Oxygenases Parents Pathway interactions Pharmaceutical Preparations Pharmacotherapy Pharmacy facility Plicamycin Proteins Reaction Recombinant Proteins Regimen Resistance Side Skeleton System Tetracyclines United States National Institutes of Health Universities Vertebral column Work analog antineoplastic antibiotics base cancer therapy catalyst chemotherapy college combinatorial cost drug discovery drug synthesis expectation glycosylation glycosyltransferase improved interest member novel novel therapeutics overexpression polyketide synthase protein structure receptor resistance mechanism scaffold screening tigecycline tool transamination

项目摘要

DESCRIPTION (provided by applicant): Natural products have a major impact on drug discovery. They have contributed to approximately 50% of new chemical entities between 1940 and 2006, because they offer a unique richness in structural skeletons combined with a high degree of chirality that has the potential to selectively match bio-receptors. Natural products have been particularly useful for the treatment of cancer and infectious diseases, nonetheless new drugs are urgently needed because current drug regimens inevitably lose their effectiveness due to resistance mechanisms. Many important natural product drugs are generated by polyketide synthases (PKS, multiple enzyme complexes), and various frame-modifying reactions, called post-PKS tailoring steps. Type II PKSs assembling multicyclic aromatic intermediates together with the respective tailoring enzymes are responsible for the generation of important drugs, such as the clinically used tetracycline antibiotics, or anthracycline and aureolic acid anticancer drugs. While type II PKSs are well studied, the post-PKS steps are much less understood, although the frame modifying enzymes typically render an inert scaffold into a bioactive drug. The primary goal of this proposal is to functionally and mechanistically characterize uniquely reacting and organized frame modifying post-PKS enzymes involved in the biosynthesis of anticancer polyketide drugs of the angucycline and aureolic acid groups. It is our expectation that uncovering the molecular details of catalysis will help to evolve these critical enzymes, so that they can be exploited to modify type II PKS scaffolds. This could lead to novel, second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis, mutasynthesis, or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.

描述（由申请人提供）：天然产品对药物发现有重大影响。在1940年至2006年之间，他们为大约50％的新化学实体做出了贡献，因为它们在结构骨架上提供了独特的丰富性，结合了高度的手性，具有选择性匹配生物受体的潜力。天然产品对于治疗癌症和传染病特别有用，尽管如此，急需新药，因为目前的药物方案不可避免地由于抗性机制而失去效力。许多重要的天然产物药物是由聚酮化合物合酶（PK，多种酶复合物）和各种框架修饰反应产生的，称为POST-PKS剪裁步骤。 II型PKS组装多环状芳香族中间体与各自的剪裁酶一起负责产生重要的药物，例如临床使用的四环素四环素抗生素，蒽环类药物和硫酸抗癌抗癌药。虽然对II型PKS进行了充分的研究，但POST-PKS步骤的理解要少得多，尽管修饰酶的框架通常会使惰性支架成为生物活性药物。该提案的主要目标是在功能和机理上表征唯一的反应和有组织的框架修饰了参与angucycline抗癌聚酯药物的生物合成的PSK酶。我们期望发现催化的分子细节将帮助进化这些关键酶，以便可以利用它们来修改II型PKS支架。这可能会导致新型的第二代“非自然”天然产物和/或天然产物的衍生物通过组合生物合成，肉类合成或化学酶合成策略。这些研究还将有助于产生新的毛霉素和吉尔伏霉素类似物，这些类似物将有助于进一步研究和引导这些药物与最近发现的特定靶标的相互作用。