NIH Director's Pioneer Award

NIH 院长先锋奖

基本信息

批准号：
7683181
负责人：
PEHR A HARBURY
金额：
$ 76.17万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683181
关键词：
Academia Acute Lymphocytic Leukemia Address Adopted Advisory Committees Affinity Affinity Chromatography Algorithms American Amino Acid Sequence Amino Acids Animal Model Antibodies Anticodon Arts Asthma Attributes of Chemicals Australia Award Basic Science Basophils Binding Biochemistry Biological Biological Availability Biological Factors Biopolymers Blast Phase Breeding CC chemokine receptor 3 California Cell Membrane Permeability Cells Chemical Engineering Chemical Evolution Chemicals Chemistry Chicago Clinic Clinical Trials Code Collaborations Collection Color Commit Communities Complex Coupled Crystallography Cysteine Cytoskeletal Filaments DNA Data Dengue Dengue Virus Deuterium Development Discipline of Nursing Disease Doctor of Medicine Doctor of Philosophy Drops Drug Prescriptions Drug resistance Economics Education Electrostatics Employment Engineering Environment Enzymes Eosinophilia Equilibrium Europe Evolution Expenditure Federal Government Figs - dietary Floods Freedom Funding Generations Genes Genetic Code Gleevec Goals Growth Human Human Resources Hydrogen Image In Vitro Individual Industry Infection Institutes Institution Interferon Receptor Interferons Journals Kilogram Kinetics Knockout Mice Knowledge Knowledge acquisition Laboratories Lead Learning Left Leucine Enkephalin Libraries Ligand Binding Ligands Location Maps Massachusetts Measurement Measures Medical Research Medicine Membrane Metabolic Methods Modeling Modification Molecular Molecular Biology Monitor Mus Myelogenous NMR Spectroscopy NS2-3 protease Names Nature Nucleic Acids Oral Organic Chemistry Organic Synthesis Pathway interactions Patients Peptide Nucleic Acids Peptide Sequence Determination Peptide aptamers Peptides Persons Phage Display Pharmaceutical Preparations Pharmacologic Substance Phase Phosphotransferases Physiology Pilot Projects Plasmids Polyribosomes Polystyrenes Population Positioning Attribute Positron-Emission Tomography Postdoctoral Fellow Price Primates Principal Investigator Probability Problem Solving Process Professional Education Property Protease Inhibitor Protein Footprinting Protein Tyrosine Kinase Proteins Protons Publications RNA Reaction Reagent Records Research Research Infrastructure Research Personnel Resistance Resolution Resources Rotation Route Running SCID Mice Scheme Science Scientist Screening for cancer Screening procedure Secure Series Shapes Signal Transduction Societies Solid Solvents Specificity Speed Staging Structure Students System T-Cell Receptor Techniques Technology Test Result Testing Therapeutic Translating Translation Process Translations Triose-Phosphate Isomerase Trust Tube Tyrosine United States United States National Institutes of Health Universities Variant Vertebral column Work Zebrafish airway hyperresponsiveness anticancer research aptamer base catalyst cell type combinatorial chemistry cost design drug development drug discovery empowered eosinophil eotaxin receptor experience falls genetic manipulation graduate student high risk high throughput screening inhibitor/antagonist insight interleukin-5 receptor kinase inhibitor knowledge base leukemia macromolecule medical schools millisecond molecular mechanics molecular recognition mouse model mutant new technology news novel olfactory receptor post-doctoral training pre-clinical professor programs protein protein interaction protein structure receptor research and development routine practice sensor small molecule structural biology technology development three dimensional structure tool trend

项目摘要

While the understanding of life at the molecular level has advanced with breathtaking speed over the last century, a practical ability to solve medical problems through molecular intervention has not developed at the same pace. The global HIV epidemic, and our inability to effectively treat cancer, both evince this basic fact. Of course, there are many reasons for this. The human body is a complex machine. We may have a list of the parts, but the function of most of them remains a mystery. Recombinant DNA technology, the scientific breakthrough that revolutionized the study of human disease, has not also provided a general prescription for treating disease. Drugs are the primary tools for this purpose, and the synthetic organic chemistry required to fashion them today is much the same as it was a century ago. Finally, the economic hurdles associated with drug discovery are daunting. This Pioneer proposal addresses a technology that can close the gap between basic research discoveries, and the application of such insights to medicine. The approach, called "chemical evolution" (see below), provides the means to breed drugs out of enormous synthetic small-molecule populations. It has the potential to transform drug discovery from a process requiring hundreds of chemist-years and the infrastructure of a large pharmaceutical company, to something a graduate student with knowledge of basic molecular biology can accomplish in a month. Chemical evolution is closely related to nucleic-acid and protein evolution techniques with proven track records in academia and industry. Moreover, our recent pilot studies have definitively established the feasibility of evolving small molecules[1-3]. These studies were the subject of two Science and Technology review articles in Chemical and Engineering News over the last year, and they were named a "Chemistry Highlight" for 2004 (a short annual compilation by the American Chemical Society of key advances in chemistry)[4-6]. Despite its enormous potential and the excitement it engenders, three different federal agencies have declined to fund further development of the technology on the grounds that it is too ambitious and too risky.

虽然在分子水平上对生命的理解不断进步上个世纪惊人的速度，解决医疗问题的实际能力通过分子干预的方法尚未以同样的速度发展。全球艾滋病毒流行病以及我们无法有效治疗癌症，都证明了这一基本事实。的当然，这有很多原因。人体是一台复杂的机器。我们可能有一份零件清单，但其中大部分的功能仍然是个谜。重组 DNA技术，彻底改变人类研究的科学突破病，还没有提供治疗疾病的通用方剂。药物是为此目的的主要工具，以及时尚所需的合成有机化学今天的他们与一个世纪前几乎没有什么不同。最后是经济障碍与药物发现相关的工作是令人畏惧的。这项先锋提案提出了一种可以缩小基本技术之间差距的技术研究发现，以及这些见解在医学上的应用。该方法，称为“化学进化”（见下文），提供了从物质中培育药物的方法巨大的合成小分子群。它具有改造药物的潜力从需要数百化学家年的过程和基础设施中发现大型制药公司，对一个研究生有基础知识的东西分子生物学可以在一个月内完成。化学演化与核酸和蛋白质进化技术在学术界和学术界拥有良好的记录行业。此外，我们最近的试点研究已经明确证实了不断演化的小分子[1-3]。这些研究是两项《科学》和《科学》杂志的主题去年化学与工程新闻中的技术评论文章，以及它们被评为 2004 年“化学亮点”（由美国化学会化学关键进展）[4-6]。尽管其规模巨大潜力及其带来的兴奋，三个不同的联邦机构已经拒绝资助该技术的进一步开发，理由是该技术过于雄心勃勃且太冒险了。