Design of Selective Substrates and Activity-Based Probes for Hydrolase Important for Pathogenesis 1 (HIP1) from Mycobacterium tuberculosis

Christian S. Lentz, Alvaro A. Ordonez, Paulina Kasperkiewicz, Florencia La Greca, Anthony J. O'Donoghue, Christopher J. Schulze, James C. Powers, Charles S. Craik, Marcin Drag, Sanjay K. Jain, Matthew Bogyo

Research output: Contribution to journalArticlepeer-review

Abstract

Although serine proteases are important mediators of Mycobacterium tuberculosis (Mtb) virulence, there are currently no tools to selectively block or visualize members of this family of enzymes. Selective reporter substrates or activity-based probes (ABPs) could provide a means to monitor infection and response to therapy using imaging methods. Here, we use a combination of substrate selectivity profiling and focused screening to identify optimized reporter substrates and ABPs for the Mtb "Hydrolase important for pathogenesis 1" (Hip1) serine protease. Hip1 is a cell-envelope-associated enzyme with minimal homology to host proteases, making it an ideal target for probe development. We identified substituted 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarins as irreversible inhibitor scaffolds. Furthermore, we used specificity data to generate selective reporter substrates and to further optimize a selective chloroisocoumarin inhibitor. These new reagents are potentially useful in delineating the roles of Hip1 during pathogenesis or as diagnostic imaging tools for specifically monitoring Mtb infections.

Original languageEnglish (US)
Pages (from-to)807-815
Number of pages9
JournalACS Infectious Diseases
Volume2
Issue number11
DOIs
StatePublished - Nov 11 2016

Keywords

  • Mycobacterium tuberculosis
  • activity-based probe
  • fluorogenic substrate
  • hydrolase important for pathogenesis 1 (Hip1)
  • protease
  • substrate profiling

ASJC Scopus subject areas

  • Infectious Diseases

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