CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies

Antibodies are created by the immune system. They recognize foreign infectious agents. Their molecular recognition capabilities make them ideal to sense and to treat diseases. They are, however, not useful in binding to and blocking the action of proteases. This is important because protease activity can trigger the development of cancers. Key proteases involved in cancer development, called matrix metalloproteases (MMPs), are overproduced during the development of cancer and during diabetes, for example. The objective of this project is to evaluate the impact of modifying antibodies with unique amino acids on the regulation of MMP activity. The education component of this proposal seeks to enhance the Tufts STEM Ambassadors program and strengthen a partnership with the biotechnology program of an area vocational/technical high school. Extracellular proteases and peptidases play key roles in human health and disease. The specific disruption of these enzymes remains a fundamental challenge. For example, matrix metalloproteinases (MMPs) play key roles in development, inflammation, cancer, and infectious disease. Highly specific inhibitors are essential for uncovering the molecular functions of enzymes and for establishing a new generation of inhibitors with improved therapeutic potential. The overall goal is to establish principles of “chemically diversified” antibodies that enable next-generation protease inhibitor discovery. This project will evaluate integration of noncanonical amino acids and yeast display technology to exploit covalent (irreversible) binding and metal binding functionalities within antibodies. The investigators hope to discover chemistries capable of interfering with enzyme functions. These studies could also identify use cases where adding chemistries to antibodies leads to inhibitors with properties (such as potency, duration of action, or specific epitope targeting) that cannot be engineered into conventional antibodies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.