![]() Our results have established this platform as a high-throughput discovery for protease inhibitory nanobodies. Our platform is designed to isolate protein-based binders, including nanobodies, antibodies, ScFvs, that can inhibit, activate, or change the substrate specificity of an enzyme. Second, I will share our recent advancements in developing a high-throughput platform to discover protein-based modulators that can reprogram a PTM-enzyme. These variants exhibit reduced activity towards a consensus sequence found in protease activatable receptors. In early results, we have isolated neurosin variants with switched specificity capable of cleaving peptide substrates found in alpha-synuclein. Such engineered enzymes could serve as modalities to investigate and treat protein aggregation diseases (synucleopathies, transthyretin amyloidosis). Our long-term goal is to engineer proteases capable of degrading aggregated proteins. In this talk, I will first present our current results on engineering the specificity of a human protease towards new targets, using a high throughput directed evolution platform called YESS 2.0. ![]() To achieve these goals, we have developed several high-throughput functional screens. We think of reprogramming a PTM-enzyme in three ways: through protein engineering to modify its biochemical properties, by functional interactions with a selective ligand, through substrate engineering and profiling. ![]() ![]() The Denard Lab aims to redefine, repurpose, and reprogram enzymes that catalyze PTMs (PTM-enzymes), with a focus on proteases and protein ligases. The ability to introduce a chemo- and regioselective post-translational modification (PTM) into a protein is foundational to our understanding of health and disease and is at the center of most chemical biology, synthetic biology, biotechnological and biomedical advances. U-M ChE faculty and graduate students are especially encouraged to attend. The ChE seminar series features guest speakers. ![]()
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