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Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators.

Satyaveni Malasala1,2, Fereshteh Azimian1,2, Yan-Hua Chen1,2,3

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Researchers discovered a new screening method to identify a wide range of homeostatic modulators (HMs) for Cdc42, a key protein in cell signaling. This approach broadens therapeutic options for various diseases by categorizing these HMs and predicting their function.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Maintaining body homeostasis is crucial for health, with homeostatic modulators (HMs) serving as key therapeutics for diseases like neuropsychiatric disorders and addiction.
  • Current HM identification is limited to membrane protein receptors and ion channels, often yielding unpredictable results.
  • The small molecule ZCL278, a partial agonist (PA), served as a model compound for developing a novel screening strategy.

Purpose of the Study:

  • To develop a novel screening method for identifying a broad spectrum of homeostatic modulators (HMs) targeting the small GTPase Cdc42.
  • To categorize identified HMs into distinct functional classes and explore their therapeutic potential.
  • To establish a predictive model for HM functionality based on molecular structural analysis.

Main Methods:

  • Utilized a Mant-GTP fluorophore-based screening assay to identify HMs for Cdc42.
  • Categorized HMs into five distinct functional classes: competitive PAs, hormetic agonists, bona fide inhibitors, bona fide activators, and ligand-enhanced agonists.
  • Employed molecular structural modeling to develop the preferential binding pocket order (PBPO) concept for profiling HMs targeting the Cdc42-intersectin (ITSN) complex.

Main Results:

  • Uncovered a comprehensive range of HMs for Cdc42, including previously understudied classes.
  • Demonstrated that identified HMs modulate bradykinin activation of Cdc42 signaling and actin remodeling.
  • Observed amelioration of Alzheimer's disease-like social behavior in a mouse model using the identified HMs.
  • The PBPO model successfully predicted the pharmacological functionality of HMs targeting Cdc42-ITSN.

Conclusions:

  • The study presents a novel, holistic screening approach for identifying diverse classes of HMs for Cdc42.
  • This method significantly broadens the therapeutic landscape for diseases involving Cdc42 dysregulation.
  • The developed PBPO concept offers a predictive tool for HM classification and drug development.