TARGETING CGMP KINASES TO DEVELOP NEW THERAPEUTICS FOR HYPERTENSIVE DISEASES

针对 CGMP 激酶开发高血压疾病新疗法

• 批准号: 8512778
• 负责人: Choel Woong Kim
• 金额: $ 18.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2014-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512778
• 关键词: Adenylate Cyclase; Adverse effects; Affinity; Architecture; Binding; Binding Sites; Cardiovascular Diseases; Cardiovascular system; Clinical; Crystallization; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Development; Dimerization; Disease; Docking; Drug Design; Drug Targeting; Enzymes; Erectile dysfunction; Escherichia coli; Failure; Flushing; Functional disorder; Generations; Goals; Guanosine Triphosphate; Headache; Heart; Heart failure; Human; Hypertension; Isoenzymes; Lead; Leukocytes; Ligands; Lung diseases; Mediating; Mind; Modeling; Molecular; Muscle Tonus; N-terminal; Natriuretic Peptides; Nature; Nitrates; Nitric Oxide; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphodiesterase Inhibitors; Phosphotransferases; Phototransduction; Platelet aggregation; Positioning Attribute; Protein Isoforms; Proteins; Pulmonary Hypertension; Purines; Reaction; Reporting; Resistance; Resolution; Second Messenger Systems; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Soluble Guanylate Cyclase; Specificity; Structure; Testing; Therapeutic; Time; Tissues; Vasodilation; Vision; Work; analog; base; cyclic GMP-binding protein; design; improved; inhibitor/antagonist; migration; molecular domain; novel therapeutics; phosphoric diester hydrolase; pulmonary arterial hypertension; purine; response; screening; second messenger; therapeutic target

DESCRIPTION (provided by applicant): The specific aims of this proposal are to obtain high-resolution structures of the cGMP binding domains of cGMP-dependent protein kinases (PKGs) and to use the structural information to design activators specific for PKG. As key receptors for cGMP, PKGs mediate most effects of cGMP elevating drugs such as nitric oxide releasing agents for the treatment of many hypertensive diseases and phosphodiesterase inhibitors for the treatment of erectile dysfunction. While PKGs are proven therapeutic targets for treating hypertensive diseases such as arterial and pulmonary hypertension, heart failure and erectile dysfunction, developing specific activators has been difficult mainly due to a lack of available structural information. In pursuit of structural information that may facilitate the development of specific activators of PKG, our group recently determined crystal structures of a fragment of the regulatory domain of human PKG I that specifically binds cGMP and activates the catalytic activity. To our knowledge, these data represent the first crystal structures known for this important domain. Our preliminary structural analysis combined with computational docking models suggests that there are many druggable sites near the cGMP binding pocket. Some docking models also suggest that derivatizing the 6- and 8-positions of the purine ring of cGMP may provide additional contacts with the protein without disrupting the existing contacts. My long-term goals are to understand the activation mechanism of PKG mediated by cGMP and to develop specific activators of PKG that can be used for treating hypertensive diseases. To achieve these goals, my plans are to determine crystals structures of the regulatory domain of PKG I (Aim #1), and to design/synthesize/test cGMP analogs that sustain the activity of PKG (Aim #2).

描述（由申请方提供）：本提案的具体目的是获得cGMP依赖性蛋白激酶（PKG）cGMP结合结构域的高分辨率结构，并使用结构信息设计PKG特异性激活剂。作为cGMP的关键受体，PKGs介导cGMP升高药物的大部分作用，例如用于治疗许多高血压疾病的一氧化氮释放剂和用于治疗勃起功能障碍的磷酸二酯酶抑制剂。虽然PKG被证明是治疗高血压疾病如动脉和肺动脉高压、心力衰竭和勃起功能障碍的治疗靶点，但主要由于缺乏可用的结构信息，开发特异性激活剂一直很困难。在追求结构信息，可以促进发展， 作为PKG的特异性激活剂，我们的小组最近确定了特异性结合cGMP并激活催化活性的人PKG I的调节结构域片段的晶体结构。据我们所知，这些数据代表了这个重要领域已知的第一个晶体结构。我们的初步结构分析结合计算对接模型表明，有许多药物位点附近的cGMP结合口袋。一些对接模型还表明，衍生化cGMP嘌呤环的6-和8-位可以提供与蛋白质的额外接触，而不破坏现有的接触。我的长期目标是了解cGMP介导的PKG激活机制，并开发可用于治疗高血压疾病的PKG特异性激活剂。为了实现这些目标，我的计划是确定PKG I调节结构域的晶体结构（目标#1），并设计/合成/测试维持PKG活性的cGMP类似物（目标#2）。