“Designer” protein-modifying enzymes for biomedicine, biotechnology and synthetic biology
Enzymes that catalyze site-specific protein modifications, including kinases, methyltransferases, proteases and protein ligases, among others, play vital roles in regulating cellular processes. Understanding the substrate specificity of these enzymes is instrumental to gain insight into their physiological mechanisms, establish potential druggable targets, and leverage or redesign their specificity. Successes along this axis would enable a variety of applications in enzyme therapeutics, biorthogonal chemistry, mass spectrometry and synthetic biology. In the Denard lab, we utilize and establish methods of protein engineering and design to redefine and redesign the substrate specificity of protein-modifying enzymes in order to repurpose them as novel therapeutic and diagnostic modalities. We expect that novel protein and cell-based therapeutic modalities will expand our toolset of biologics for management of chronic illnesses, inflammations and cancer.
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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.
Moreover, using engineered protein-modifying enzymes, we seek to build protein circuits that reprogram cellular behavior along rapid time scales. Modular, responsive and predictable synthetic protein circuits will augment genetic engineering by introducing novel design principles that will facilitate their integration into larger cellular networks. In a related area of research, we aim to evolve enzymes for the site-specific conjugations to proteins, cells and biomaterials. We envision to generate highly-functionalized therapeutic agents with multipronged and synergistic modes of action. |
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