TARGETING CGMP KINASES TO DEVELOP NEW THERAPEUTICS FOR HYPERTENSIVE DISEASES

描述(申请人提供)：本方案的具体目的是获得cGMP依赖的蛋白激酶(PKG)的cGMP结合域的高分辨率结构，并利用这些结构信息设计PKG的特异性激活剂。作为cGMP的关键受体，pKGS介导了cGMP升高药物的大部分作用，如治疗多种高血压疾病的一氧化氮释放药和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的治疗靶点，如动脉和肺动脉高压、心力衰竭和勃起功能障碍，但开发特定的激活剂一直很困难，主要是因为缺乏可用的结构信息。为了寻求可能有助于发展的结构性信息 为了研究PKG的特异性激活剂，本课题组最近确定了人PKG I调节域的一个片段的晶体结构，该片段能与cGMP特异结合并激活其催化活性。据我们所知，这些数据代表了已知的这一重要领域的第一批晶体结构。我们的初步结构分析结合计算对接模型表明，在cGMP结合口袋附近有许多可药物的部位。一些对接模型还表明，衍生cGMP的嘌呤环的6位和8位可能会在不破坏现有接触的情况下提供与蛋白质的额外接触。我的长期目标是了解cGMP介导的PKG的激活机制，并开发出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)。

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).