Giuseppe Tagliaferro, Maria Giulia Davighi, Francesca Clemente, Filippo Turchi, Marco Schiavina, Camilla Matassini, Andrea Goti, Amelia Morrone, Roberta Pierattelli, Francesca Cardona, Isabella C Felli
{"title":"Evidence of α-Synuclein/Glucocerebrosidase Dual Targeting by Iminosugar Derivatives.","authors":"Giuseppe Tagliaferro, Maria Giulia Davighi, Francesca Clemente, Filippo Turchi, Marco Schiavina, Camilla Matassini, Andrea Goti, Amelia Morrone, Roberta Pierattelli, Francesca Cardona, Isabella C Felli","doi":"10.1021/acschemneuro.4c00618","DOIUrl":null,"url":null,"abstract":"<p><p>Intrinsically disordered proteins (IDPs) are highly flexible molecules often linked to the onset of incurable diseases. Despite their great therapeutic potential, IDPs are often considered as undruggable because they lack defined binding pockets, which constitute the basis of drug discovery approaches. However, small molecules that interact with the intrinsically disordered state of α-synuclein, the protein linked to Parkinson's disease (PD), were recently identified and shown to act as chemical chaperones. Glucocerebrosidase (GCase) is an enzyme crucially involved in PD, since mutations that code for GCase are among the most frequent genetic risk factors for PD. Following the \"dual-target\" approach, stating that one carefully designed molecule can, in principle, interfere with more than one target, we identified a pharmacological chaperone for GCase that interacts with the intrinsically disordered monomeric form of α-synuclein. This result opens novel avenues to be explored in the search for molecules that act on dual targets, in particular, with challenging targets such as IDPs.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1251-1257"},"PeriodicalIF":4.1000,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acschemneuro.4c00618","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/13 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Intrinsically disordered proteins (IDPs) are highly flexible molecules often linked to the onset of incurable diseases. Despite their great therapeutic potential, IDPs are often considered as undruggable because they lack defined binding pockets, which constitute the basis of drug discovery approaches. However, small molecules that interact with the intrinsically disordered state of α-synuclein, the protein linked to Parkinson's disease (PD), were recently identified and shown to act as chemical chaperones. Glucocerebrosidase (GCase) is an enzyme crucially involved in PD, since mutations that code for GCase are among the most frequent genetic risk factors for PD. Following the "dual-target" approach, stating that one carefully designed molecule can, in principle, interfere with more than one target, we identified a pharmacological chaperone for GCase that interacts with the intrinsically disordered monomeric form of α-synuclein. This result opens novel avenues to be explored in the search for molecules that act on dual targets, in particular, with challenging targets such as IDPs.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research