发展高活性、高选择性及良好类药性的组织蛋白酶D(Cath D)抑制剂，对阐明该蛋白酶的生物学功能及与相关疾病的关系具有重要意义。我们前期以含有独特结构的海洋多肽为模板，通过全合成及初步结构优化，发现了酶水平活性在pM级的Cath D选择性抑制剂。本项目拟在此基础上开展如下研究：根据分子对接的结果对苗头化合物进行结构简化，确定结构最简活性片段；然后通过残基骈合、电子等排、Freidinger肽局部构象限制及环化整体构象限制等拟肽化策略，进一步提高分子的选择性和类药性；以优化后的分子为化学探针，依次在分子水平、细胞水平上对Cath D的生物学功能进行初步研究，然后优选1-2个分子在动物水平进行初步的验证。本项目的开展将为探究Cath D的可靶性提供重要依据，且有助于深度挖掘海洋天然产物的研究价值。

The development of high quality (high potent, selective and drug-like) Cathepsin D (Cath D) inhibitors is of great significance to its biological function studies and the correlation of Cath D and related diseases. In previous investigation, we finished the total synthesis and primary structural optimization of a marine peptide bearing special fragments. These studies led to the discovery of a selective and high potent Cath D inhibitor (IC50 at pM level). Based on these results, we will focus on the following studies in this project. Firstly, validating the minimal fragment of bioactive molecules by structural simplification with the assistance of CADD. Then we will focus on enhancing selectivity and drug-like properties of this hit by residue fused, bioisosteres, and conformational restriction. The resultant highly drug-like candidate will be used as chemical probe for preliminary study of Cath D functions. This project will afford new reference for the target validation of Cath D, and will take full advantage of marine natural products.