Age-related Macular Degeneration (AMD) is the leading cause of visual impairment in the industrialized world. Nearly 200 million people worldwide are projected to be living with AMD by 2020, highlighting the importance of further development of treatments for this debilitating disease. The deregulated expression and activity of a well-characterized serine protease, HtrA1, has been linked to the onset of AMD, as well as to some cancers and neurodegenerative diseases, making HtrA1 a potential target for drug therapy. Our initial research has been focused on the cloning, expression, purification, and crystallization of recombinant HtrA1, to allow for structure-based drug discovery efforts. We have optimized our expression and purification for HtrA1 and have been able to refine a crystallization condition allowing us to reproducibly generate large amounts of quality protein crystals. Our HtrA1 crystals diffracted to 2.75 Å resolution, and we have since begun to conduct computational-aided structure-based drug discovery to predict high affinity binding molecules. We test these predicted compounds <i>in vitro</i> using both thermal shift and enzymatic activity assays, looking for high-affinity binding as well as potent inhibition. We have identified leads from these <i>in vitro</i> assays, and are working to co-crystallize and/or soak these compounds into our crystals in order to define the 3-dimensional ligand:protein interactions. After determining these interactions, we will work towards chemical refinement of these leads to make them more specific, potent, and targeted for HtrA1 to push forward the potential for novel therapeutics for AMD.

Structure-based drug discovery for HtrA1: Novel age-related macular degeneration target

2019 Fall National Meeting

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