Human cathepsin D (HCD), a lysosomal aspartic peptidase, plays an important role in tumor progression and metastasis. It is an independent marker of poor prognosis in breast cancer. HCD is overexpressed and hyper-secreted in cancer cells and is involved in proteolysis of various intra- and extracellular factors and matrix remodeling. Our work is focused on the development of HCD inhibitors as novel tools for HCD regulation. We designed and synthesized a set of macrocyclic peptidomimetic inhibitors that were used for analysis of the macrocyclic scaffold and specificity of S1 and S2´ subsites. The high resolution crystal structures of three macrocyclic inhibitors in complex with HCD were determined and their binding mode was investigated using quantum chemical calculations. The work identified a novel inhibitor scaffold and interaction hot spots that can be exploited for the rational design of specific inhibitors of HCD and related aspartic peptidases as potential chemotherapeutics.
This work was supported by the project InterBioMed LO1302 from the Ministry of Education of the Czech Republic, and institutional project RVO 61388963.