Summary

This project aims to develop specific inhibitors to treat AMD patients based on the protein structure and the natural substrate specificity profile of HTRA1. The aim 1 of this study is to determine the atomic-resolution structure of the HTRA1 PC-PDZ domain trimer using cryogenic electron microscopy (Cryo-EM), which will establish the empirical basis for a structure-function guided drug development. The aim 2 of this study is to design and test peptidomimetics (peptide-like compounds) derived from the natural substrate specificity profile of HTRA1 in choroid based on proteomic analysis. The compounds will be tested in eye tissue derived from human stem cells with AMD mutations.

Project Details

There are no HTRA1 specific inhibitors targeting the two functional domains (i.e., protease core domain and PDZ domain) at the same time. Moreover, our inhibitors may exclusively target the AMD-specific pathway of HTRA1 in patients since the compounds' design-origin is the choroidal substrates of HTRA1. We expect the success of this study will result in a therapeutic candidate for AMD, which will be especially beneficial for the patients that have a high-AMD-risk-factor gene mutation in HTRA1. In addition, this study will provide atomic-resolution protein structures of the HTRA1 PC-PDZ domain, which will establish the molecular and mechanistic basis to better understand the HTRA1-dependent pathology in AMD, Alzheimer's disease, and arthritis.