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Dissecting biological pathways in cancer and bacteria through the study and application of serine protease inhibitors

  • Author(s): Ray, Manisha
  • Advisor(s): Craik, Charles S
  • et al.

Serine proteases are an abundant class of enzymes that are vital to many biological processes. Proteolysis must be tightly controlled, and this regulation is frequently carried out through serine protease inhibitors. Dysregulation of either the protease or the inhibitor can have severe biological consequences, such as the development of cancer. Additionally, the role of proteases can be challenging to study, since the active form or proteases can be difficult to isolate. In this thesis, the role of the naturally occurring protease inhibitor PI-9 is examined in the development of prostate cancer. The findings presented here show that PI-9 protects prostate cancer cells from immunosurveillance early in cancer progression. Additionally, a chemical biology approach is taken to develop small molecule activity based probes for serine proteases, in order to better study active proteases in complex systems. Principles governing the design and potency of these probes were discovered, and new imaging applications for these probes were developed. These new techniques could be applied to the study of proteases in any biological system. The work described here provides new information on how to identify proteases involved in cancer and bacterial development, and such insights could be used to design new therapeutic strategies.

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