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: 8384906
• 负责人: Choel Woong Kim
• 金额: $ 23.48万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384906
• 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 Delivery Systems; Drug Design; 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; Screening procedure; 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; 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). PUBLIC HEALTH RELEVANCE: cGMP-dependent protein kinase (PKG) is the central enzyme of NO-cGMP signaling pathway that regulates platelet aggregation, smooth muscle tone, phototransduction, and leukocyte migration. Although PKG has been heavily targeted for treating diseases such as erectile dysfunction and cardiovascular and pulmonary diseases, developing specific activators and inhibitors has been difficult because there is no structural information available. My ultimate goal is to rationally target the kinase by obtaining high-resolution crystal structures of PKG and its isozymes and develop pharmacological agents that can modulate the activity of the kinase to treat diseases related to NO-cGMP signaling dysfunction.

描述（由申请人提供）：本提案的具体目的是获得 cGMP 依赖性蛋白激酶（PKG）的 cGMP 结合域的高分辨率结构，并利用该结构信息设计 PKG 特异性的激活剂。作为 cGMP 的关键受体，PKG 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 已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，但开发特定的激活剂一直很困难，主要是由于缺乏可用的结构信息。寻求可能促进开发的结构信息 作为 PKG 的特异性激活剂，我们小组最近确定了人 PKG I 调节域片段的晶体结构，该片段特异性结合 cGMP 并激活催化活性。据我们所知，这些数据代表了该重要领域的第一个已知晶体结构。我们的初步结构分析结合计算对接模型表明 cGMP 结合袋附近有许多可成药位点。一些对接模型还表明，衍生化 cGMP 嘌呤环的 6 和 8 位可能会提供与蛋白质的额外接触，而不会破坏现有的接触。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特异性PKG激活剂。为了实现这些目标，我的计划是确定 PKG I 监管域的晶体结构（目标#1），并设计/合成/测试维持 PKG 活性的 cGMP 类似物（目标#2）。 公共健康相关性：cGMP 依赖性蛋白激酶 (PKG) 是 NO-cGMP 信号通路的核心酶，可调节血小板聚集、平滑肌张力、光转导和白细胞迁移。尽管 PKG 已被广泛用于治疗勃起功能障碍以及心血管和肺部疾病等疾病，但由于没有可用的结构信息，开发特定的激活剂和抑制剂一直很困难。我的最终目标是通过获得 PKG 及其同工酶的高分辨率晶体结构来合理靶向激酶，并开发可以调节激酶活性的药物制剂，以治疗与 NO-cGMP 信号传导功能障碍相关的疾病。