Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators

Satyaveni Malasala; Fereshteh Azimian; Yan-Hua Chen; Jeffery L Twiss; Christi Boykin; Shayan Nik Akhtar; Qun Lu

doi:10.1038/s42004-024-01352-7

Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators

Commun Chem. 2024 Nov 19;7(1):271. doi: 10.1038/s42004-024-01352-7.

Authors

Satyaveni Malasala^#^{1

2}, Fereshteh Azimian^#^{1

2}, Yan-Hua Chen^{1

2

3}, Jeffery L Twiss^{4

5}, Christi Boykin¹, Shayan Nik Akhtar¹, Qun Lu^{6

7

8

9

10}

Affiliations

¹ Department of Chemistry and Biochemistry, College of Arts and Sciences, University of South Carolina, Columbia, SC, USA.
² Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Biological Sciences, College of Arts and Sciences, University of South Carolina, Columbia, SC, USA.
⁵ Carolina Autism and Neurodevelopment Center, University of South Carolina, Columbia, SC, USA.
⁶ Department of Chemistry and Biochemistry, College of Arts and Sciences, University of South Carolina, Columbia, SC, USA. qun@mailbox.sc.edu.
⁷ Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA. qun@mailbox.sc.edu.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. qun@mailbox.sc.edu.
⁹ The Harriet and John Wooten Laboratory for Alzheimer's and Neurodegenerative Diseases Research, The Brody School of Medicine, East Carolina University, Greenville, NC, USA. qun@mailbox.sc.edu.
¹⁰ Laboratory of Molecular Neurotherapeutics, Center for Neurotherapeutics, University of South Carolina, Columbia, SC, USA. qun@mailbox.sc.edu.

^# Contributed equally.

Abstract

Maintaining body homeostasis is the ultimate key to health. There are rich resources of bioactive materials for the functionality of homeostatic modulators (HMs) from both natural and synthetic chemical repertories^1-3. HMs are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction (e.g. Buspirone and benzodiazepines)^4-7. However, the identification of therapeutic HMs are often unpredictable and limited to membrane protein receptors and ion channels. Based on a serendipitously encountered small molecule ZCL278 with partial agonist (PA) profile as a model compound^8-10, the Mant-GTP fluorophore-based Cdc42-GEF (guanine nucleotide exchange factor) screening uncovered a near holistic spectrum of HMs for Cdc42, a cytoplasmic small GTPase in the Ras superfamily^11,12. We categorized these HMs as functionally distinct, with some previously understudied classes: Class I-competitive PAs, Class II-hormetic agonists, Class III-bona fide inhibitors, Class IV-bona fide activators, and Class V-ligand-enhanced agonists. The model HMs elicited striking biological functionalities in modulating bradykinin activation of Cdc42 signaling as well as actin remodeling while they ameliorated Alzheimer's disease-like social behavior in mouse model. Furthermore, molecular structural modeling analyses led to the concept of preferential binding pocket order (PBPO) for profiling HMs that target Cdc42 complexed with intersectin (ITSN), a GEF selectively activating Cdc42. Remarkably, the PBPO enabled a prediction of HM class that mimics the pharmacological functionality. Therefore, our study highlights a model path to actively capture different classes of HM to broaden therapeutic landscape.

Abstract

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