In one area of focus, we aim to evolve the specificity of proteases to target misfolded and aberrant proteins involved in neurodegenerative, autoimmune diseases and cancer. We hypothesize that catalytic degradation of disease-related proteins can fight diseases in ways that can be complementary to and mechanistically distinct from current therapeutic approaches. Unlike antibodies and small molecules, proteases can catalytically degrade their targets, making them attractive therapeutic agents that would enable novel strategies to target diseases. Protease substrate specificity engineering represents a major step in the design of therapeutic proteases.
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An important question in drug discovery is whether one can reprogram the substrate preference and activity of an enzyme rather than completely inhibiting its catalytic activity. Substrate-selective modulation could represent a paradigm shift in how we target diseases such as diabetes, Alzheimer’s and heart disease. The Denard Lab is developing high-throughput functional screens and statistical machine learning approaches to concurrently map enzyme distal regulation, discover and ultimately predict properties of ligand that elicit, induce, and stabilize substrate-selective conformations.
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