TARGETING CGMP KINASES TO DEVELOP NEW THERAPEUTICS FOR HYPERTENSIVE DISEASES

描述（由申请人提供）：本申请的具体目的是获得cGMP依赖性蛋白激酶（PKGs）的cGMP结合域的高分辨率结构，并利用结构信息设计特异性的PKG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，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PKGs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，可能促进发展

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.