Satyaveni Malasala, Fereshteh Azimian, Yan-Hua Chen, Jeffery L. Twiss, Christi Boykin, Shayan Nik Akhtar, Qun Lu
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Based on a serendipitously encountered small molecule ZCL278 with partial agonist (PA) profile as a model compound8–10, 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 superfamily11,12. 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. Homeostatic modulators (HMs) are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction; however, their discovery is often unpredictable and limited to membrane protein receptors and ion channels. Here, the authors analyze a spectrum of novel HMs for Cdc42, a cytoplasmic small GTPase in the Ras superfamily, with striking biological functionalities and potential therapeutic applications.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-11"},"PeriodicalIF":5.9000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01352-7.pdf","citationCount":"0","resultStr":"{\"title\":\"Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators\",\"authors\":\"Satyaveni Malasala, Fereshteh Azimian, Yan-Hua Chen, Jeffery L. Twiss, Christi Boykin, Shayan Nik Akhtar, Qun Lu\",\"doi\":\"10.1038/s42004-024-01352-7\",\"DOIUrl\":null,\"url\":null,\"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 repertories1–3. 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 compound8–10, 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 superfamily11,12. 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. Homeostatic modulators (HMs) are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction; however, their discovery is often unpredictable and limited to membrane protein receptors and ion channels. 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Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators
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 repertories1–3. 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 compound8–10, 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 superfamily11,12. 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. Homeostatic modulators (HMs) are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction; however, their discovery is often unpredictable and limited to membrane protein receptors and ion channels. Here, the authors analyze a spectrum of novel HMs for Cdc42, a cytoplasmic small GTPase in the Ras superfamily, with striking biological functionalities and potential therapeutic applications.
期刊介绍:
Communications Chemistry is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the chemical sciences. Research papers published by the journal represent significant advances bringing new chemical insight to a specialized area of research. We also aim to provide a community forum for issues of importance to all chemists, regardless of sub-discipline.