Niv Papo
Ben-Gurion University of the Negev, Israel
Title: Rational and combinatorial engineering of protease inhibitors for cancer imaging and therapy
Biography
Biography: Niv Papo
Abstract
Mesotrypsin, an enzyme that contributes to progression and metastasis ofmany cancers,constitutes a compelling therapeutic target. However, with its unique capability for cleavage and inactivation of proteinaceous inhibitors, mesotrypsin presents a formidable challenge to the development of biologic inhibitors.Our study identifies a promising mesotrypsin inhibitor – a triple mutant of the human amyloid precursor protein Kunitz protease inhibitor domain (APPI) with superior affinity, specificity, and proteolytic stability – as a starting point for the development of anticancer protein therapeutics. We demonstrate that the mutant acts as a functional inhibitor of mesotrypsin-dependent prostate cancer cellular invasiveness. Additionally, the crystal structure of the mutant/mesotrypsin complex provides new insights into the structural and mechanistic basis for the mutant's improved binding and proteolytic resistance. Finally, the study establishes proof-of-principle for a novel library screening approach that is widely applicable for simultaneously evolving proteolytic stability and a desired functionality for diverse protein scaffolds.