Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the...

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• The mitochondrial ClpP protease regulates protein quality control and is upregulated in cancer cells.
• ClpP overexpression aids cancer cells by degrading reactive oxygen species (ROS)-damaged proteins, supporting oncogenesis.
• Targeting ClpP with small-molecule agonists is a promising cancer therapy strategy.

Purpose of the Study:

• To synthesize and characterize novel imipridone-derived compounds as potential ClpP inhibitors.
• To elucidate the structural and molecular mechanisms of ClpP inhibition by these compounds.
• To investigate the impact of ClpP dysregulation on cancer cell viability and proliferation.

Main Methods:

• Synthesis and characterization of imipridone-derived compounds.
• Biochemical, biophysical, and cellular assays to assess compound activity.
• X-ray crystallography to determine compound-ClpP binding interactions.
• N-terminome profiling to analyze proteomic changes in cancer cells.

Main Results:

• Imipridone compounds demonstrated enhanced binding affinity to ClpP due to improved shape and charge complementarity.
• X-ray crystallography revealed specific binding interactions within ClpP's hydrophobic pockets.
• N-terminome profiling identified global proteomic alterations and specific cleavage motifs upon compound treatment.
• Dysregulated ClpP activity significantly affected cancer cell viability and proliferation.

Conclusions:

• The synthesized imipridone compounds effectively target and modulate mitochondrial ClpP protease activity.
• Structural insights explain the enhanced binding of these compounds to ClpP.
• Understanding ClpP's role in cancer provides a basis for developing new therapeutic strategies targeting protein homeostasis.