Academic Journal
Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.
| Τίτλος: | Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond. |
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| Συγγραφείς: | Czuba M; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688, Poland., Szafrańska K; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688, Poland., Kolaczkowski M; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688, Poland., Marcinkowska M; Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688, Poland. Electronic address: monika.marcinkowska@uj.edu.pl. |
| Πηγή: | European journal of medicinal chemistry [Eur J Med Chem] 2026 Oct 05; Vol. 315, pp. 118951. Date of Electronic Publication: 2026 May 14. |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| Ιατρικοί όροι (MeSH): | Transient Receptor Potential Channels*/metabolism , Transient Receptor Potential Channels*/antagonists & inhibitors , Transient Receptor Potential Channels*/agonists , Neurodegenerative Diseases*/drug therapy , Neurodegenerative Diseases*/metabolism , Lysosomal Storage Diseases*/drug therapy , Lysosomal Storage Diseases*/metabolism , Small Molecule Libraries*/pharmacology , Small Molecule Libraries*/chemistry , Lysosomes*/drug effects , Lysosomes*/metabolism, Humans ; Ligands ; Animals ; Molecular Structure |
| Περίληψη: | TRPML1, a lysosomal Ca2+ channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics. (Copyright © 2026 Elsevier Masson SAS. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Monika Marcinkowska reports financial support was provided by Jagiellonian University in Kraków Medical College. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Lysosomal dysfunction; Lysosomal storage disorders; Neurodegenerative diseases; Protein aggregates; TRPML1 agonist |
| Substance Nomenclature: | 0 (Transient Receptor Potential Channels) 0 (Small Molecule Libraries) 0 (Ligands) 0 (MCOLN1 protein, human) |
| Entry Date(s): | Date Created: 20260519 Date Completed: 20260716 Latest Revision: 20260716 |
| Update Code: | 20260717 |
| DOI: | 10.1016/j.ejmech.2026.118951 |
| PMID: | 42155171 |
| Βάση Δεδομένων: | MEDLINE |
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