Search for novel PKC ligands as therapeutic seeds for intractable diseases

参与细胞信号转导的蛋白激酶C （PKC）是治疗癌症和阿尔茨海默病的靶酶之一。为了探索具有新骨架的PKC配体，我们利用PKC C1结构域的合成肽筛选系统，成功地从日本苔藓虫Bugula neritina中鉴定出几种抗肿瘤的海洋大环内酯类苔藓抑素。苔藓抑素4、10和14的结构活性研究表明，C20位置的酯基不是结合和激活PKC所必需的。此外，我们还从海绵中筛选了新的PKC配体，并发现了一种海绵体。含有PKC配体，具有与苔藓抑素相当的高结合亲和力。

Protein kinase C (PKC) involved in cellular signal transduction is one of the target enzymes fortherapeutics of cancer and Alzheimer’s disease. To explore PKC ligands with novel skeleton, we employed our screening system utilizing synthetic peptides of PKC C1 domains, to succeed to identify several bryostatins, anti-neoplastic marine macrolides, from Japanese bryozoan Bugula neritina. Structure-activity studies of bryostatins 4, 10 and 14 suggested that the ester group at position C20 was not necessary for binding to and activating PKC. Moreover, we screened novel PKC ligands from marine sponges, and found that a marine sponge Theonellasp. contains PKC ligands with high binding affinitycomparable to bryostatins.