Rational Design of Adenylation Enzyme Inhibitors

腺苷酸化酶抑制剂的合理设计

基本信息

批准号：
8373088
负责人：
DEREK S TAN
金额：
$ 48.14万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8373088
关键词：
Active Sites Address Amides Amino Acids Amino Acyl-tRNA Synthetases Anabolism Anhydrides Anti-Bacterial Agents Bacteria Binding Biochemistry Biological Biological Factors Biological Process Cancer Biology Carboxylic Acids Cardiovascular Diseases Cardiovascular system Catalysis Cells Chemicals Clinical Trials Coenzyme A Ligases Communicable Diseases Complex Development Electron Transport Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Esters Fatty Acids Glycolipids Goals Gram-Positive Bacteria Gram-Positive Bacterial Infections Individual Interdisciplinary Study Life Lysine Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolism Microbiology Molecular Molecular Conformation Mupirocin Mycobacterium tuberculosis Nature Neurodegenerative Disorders Nucleic Acid-Independent Peptide Biosynthesis Organic Synthesis Pathway interactions Peptides Permeability Pharmaceutical Chemistry Pharmacology Phase Play Process Property Proteins Quinones Reaction Research Role Siderophores Staphylococcus aureus Structure Structure-Activity Relationship Text Therapeutic Topical Antibiotic Translations Ubiquitin Ubiquitination Variant Virulence Factors Vitamin K 2 Work acyl group adenylate analog ascamycin base cancer therapy design drug discovery immunopathology infectious disease treatment inhibitor/antagonist insight interest methicillin resistant Staphylococcus aureus new therapeutic target novel peptide synthase preclinical evaluation programs protein folding protein function small molecule structural biology thioester uptake

项目摘要

DESCRIPTION (provided by applicant): Rational Design of Adenylation Enzyme Inhibitors Adenylation enzymes play central roles in diverse biological pathways across all three domains of life, mediating processes such as protein translation, fatty acid and amino acid metabolism, natural product biosynthesis, and ubiquitin conjugation. These enzymes catalyze a two-step reaction involving initial ATP- dependent adenylation of a carboxylic acid substrate to form a tightly-bound acyl-AMP (acyl adenylate) intermediate, followed by attack of a nucleophile on this mixed anhydride to form an ester, thioester, or amide product. Strikingly, while all adenylation enzymes catalyze this same general reaction, at least six distinct protein folds have been identified within this mechanistic superfamily. Inhibitors of adenylation enzymes have important potential biomedical applications in infectious diseases, cancer, cardiovascular disease, metabolic disease, immunopathologies, and neurodegenerative disorders. We propose herein to continue our successful, long-term program on the rational design of adenylation enzyme inhibitors. We are advancing an inhibitor design platform that leverages mechanistic and structural information and is general for all classes of adenylation enzymes. Our previous efforts have yielded novel antibacterials targeting bacterial siderophore, glycolipid, and menaquinone biosynthesis. We have also developed semisynthetic protein inhibitors of ubiquitin/ubiquitin-like modifier E1 activating enzymes that have provided profound mechanistic insights into the functions of these enzymes. Our goals for the next project period are to develop selective inhibitors of non-ribosomal peptide biosynthesis using a macrocyclic design, to develop optimized menaquinone biosynthesis inhibitors as new antibacterials, and to develop protein-based and small-molecule inhibitors of E1 activating enzymes to probe their molecular mechanisms and biological functions in cancer. Systematic correlation of physicochemical properties with bacterial uptake will also be studied. This work will have broad impacts in structure-based design, antibacterial medicinal chemistry, and enzymology, and will be carried out through established multidisciplinary collaborations comprising combined expertise in organic synthesis, medicinal chemistry, pharmacology, biochemistry, microbiology, and structural biology. PUBLIC HEALTH RELEVANCE: Rational Design of Adenylation Enzyme Inhibitors Adenylation enzymes play central roles in numerous biological processes and are promising new therapeutic targets for the treatment of infectious diseases, cancer, cardiovascular disease, metabolic disease, immunopathologies, and neurodegenerative disorders. The proposed research aims to design novel chemical inhibitors of three classes of adenylation enzymes to probe their biological functions and to evaluate their potential in antibacterial and anticancer therapy.

描述（由申请人提供）：腺苷酸化酶抑制剂的合理设计腺苷酸化酶在生命的所有三个领域的多种生物途径中起着核心作用，介导过程，例如蛋白质翻译，脂肪酸和氨基酸代谢，天然产物生物合成以及尿素结合蛋白结合素，。这些酶催化了涉及羧酸底物初始ATP依赖性腺苷酸化的两步反应，形成紧密结合的酰基 - 酰基AMP（酰基腺苷酸）中间体，然后在这种混合的赤道酸盐上攻击这种混合的酸酐，以形成酯，泰氏酯，泰可，泰可，泰可，，或酰胺产品。令人惊讶的是，尽管所有腺苷酸化酶都催化了同样的一般反应，但在该机械性超家族中已经鉴定出了至少六个不同的蛋白质褶皱。腺苷酸化酶的抑制剂在传染病，癌症，心血管疾病，代谢疾病，免疫病理学和神经退行性疾病中具有重要的潜在生物医学应用。我们在此提议继续我们在腺苷酸化酶抑制剂合理设计方面取得成功的长期计划。我们正在推进一个利用机械和结构信息的抑制剂设计平台，并且对于所有类别的腺苷酸化酶都是一般的。我们以前的努力产生了针对细菌铁载体，糖脂和梅纳金酮生物合成的新型抗菌物。我们还开发了泛素/泛素样修饰剂E1激活酶的半合成蛋白抑制剂，这些酶为这些酶的功能提供了深刻的机械见解。 Our goals for the next project period are to develop selective inhibitors of non-ribosomal peptide biosynthesis using a macrocyclic design, to develop optimized menaquinone biosynthesis inhibitors as new antibacterials, and to develop protein-based and small-molecule inhibitors of E1 activating enzymes to probe它们在癌症中的分子机制和生物学功能。还将研究物理化学特性与细菌摄取的系统相关性。这项工作将对基于结构的设计，抗菌药物化学和酶促产生广泛的影响，并将通过既定的多学科合作进行，包括有机合成，药物化学，药理学，生物化学，微生物学和结构生物学的综合专业知识。公共卫生相关性：腺苷酸化酶抑制剂腺苷酸化酶在众多生物学过程中起着核心作用，并有望在治疗传染病，癌症，心血管疾病，代谢性疾病，免疫病毒和神经脱发的新治疗靶点中起着核心作用。拟议的研究旨在设计三类腺苷酸化酶的新型化学抑制剂，以探测其生物学功能，并评估其在抗菌和抗癌治疗中的潜力。