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Area of Science:

  • Medicinal Chemistry
  • Immunology
  • Structural Biology

Background:

  • Cathepsin S (CatS) plays a crucial role in modulating the adaptive immune system.
  • Dysregulation of CatS is implicated in various major diseases.
  • Targeting CatS offers a specific approach for immune system modulation.

Purpose of the Study:

  • To synthesize novel, highly selective inhibitors of Cathepsin S (CatS).
  • To achieve potent enzymatic and cellular activity for therapeutic development.
  • To explore structure-activity relationships for optimizing inhibitor design.

Main Methods:

  • Utilized Nuclear Magnetic Resonance (NMR) fragment screening to identify initial hits.
  • Employed crystal structure-aided merging for rational inhibitor design.
  • Synthesized and characterized novel CatS inhibitors.
  • Assessed enzymatic inhibition (Ki values) and functional activity in human Raji cells.

Main Results:

  • Discovered novel CatS inhibitors with picomolar enzymatic Ki values.
  • Achieved nanomolar functional activity in human Raji cells.
  • Identified binding hotspots using noncovalent fragment hits.
  • Established structure-activity relationships for covalent inhibitors, enabling potency optimization.

Conclusions:

  • Successfully synthesized highly selective CatS inhibitors with significant potency.
  • The developed inhibitors demonstrate potential for therapeutic applications in CatS-mediated diseases.
  • Integrated fragment screening and structural biology approaches accelerate the discovery of potent drug candidates.