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）：该提案的具体目的是获得CGMP依赖性蛋白激酶（PKG）的CGMP结合结构域的高分辨率结构，并将结构信息用于设计针对PKG的激活剂。作为CGMP的关键受体，PKG介导了CGMP升高药物的大多数作用，例如一氧化氮释放剂，用于治疗许多高血压疾病和磷酸二酯酶抑制剂，以治疗勃起功能障碍。虽然PKG被证明是治疗高血压疾病（例如动脉和肺动脉高压，心力衰竭和勃起功能障碍）的治疗靶标，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。追求可能有助于发展的结构信息 PKG的特定激活剂，我们的组最近确定了人类PKG I调节结构域的片段的晶体结构，该片段专门结合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已知的第一个晶体结构。我们的初步结构分析与计算对接模型相结合，表明CGMP结合口袋附近有许多可药物的位点。一些对接模型还表明，CGMP嘌呤环的6个位置和8位可能会提供与蛋白质的其他接触，而不会破坏现有的接触。我的长期目标是了解CGMP介导的PKG的激活机制，并开发可用于治疗高血压疾病的PKG的特定活化剂。为了实现这些目标，我的计划是确定PKG I（AIM＃1）调节域的晶体结构，并设计/合成/测试CGMP类似物，以维持PKG的活动（AIM＃2）。 公共卫生相关性：CGMP依赖性蛋白激酶（PKG）是调节血小板聚集，平滑肌张力，光转导和白细胞迁移的NO-CGMP信号通路的中心酶。尽管PKG已被旨在治疗诸如勃起功能障碍以及心血管和肺部疾病之类的疾病，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，并开发可以调节激酶的活性以治疗与NOCMP信号传导功能障碍相关的疾病的药理剂，从而合理地靶向激酶。