Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

Human cathepsin D
(CatD), a pepsin-family aspartic protease, plays
an important role in tumor progression and metastasis. Here, we report
the development of biomimetic inhibitors of CatD as novel tools for
regulation of this therapeutic target. We designed a macrocyclic scaffold
to mimic the spatial conformation of the minimal pseudo-dipeptide
binding motif of pepstatin A, a microbial oligopeptide inhibitor,
in the CatD active site. A library of more than 30 macrocyclic peptidomimetic
inhibitors was employed for scaffold optimization, mapping of subsite
interactions, and profiling of inhibitor selectivity. Furthermore,
we solved high-resolution crystal structures of three macrocyclic
inhibitors with low nanomolar or subnanomolar potency in complex with
CatD and determined their binding mode using quantum chemical calculations.
The study provides a new structural template and functional profile
that can be exploited for design of potential chemotherapeutics that
specifically inhibit CatD and related aspartic proteases.