| Full text | |
| Author(s): |
Cunha, Micael R.
;
Do Amaral, Bruno S.
;
Takarada, Jessica E.
;
Valderrama, Gabriel V.
;
Batista, Andrea N. L.
;
Batista Jr, Joao M.
;
Cass, Quezia B.
;
Counago, Rafael M.
;
Massirer, Katlin B.
Total Authors: 9
|
| Document type: | Journal article |
| Source: | CHEMBIOCHEM; v. 25, n. 22, p. 7-pg., 2024-08-12. |
| Abstract | |
Autophagic flux plays a crucial role in various diseases. Recently, the lysosomal ion channel TRPML1 has emerged as a promising target in lysosomal storage diseases, such as mucolipidosis. The discovery of mucolipin synthetic agonist-1 (ML-SA1) has expanded our understanding of TRPML1 ' s function and its potential therapeutic uses. However, ML-SA1 is a racemate with limited cellular potency and poor water solubility. In this study, we synthetized rac-ML-SA1, separated the enantiomers by chiral liquid chromatography and determined their absolute configuration by vibrational circular dichroism (VCD). In addition, we focused on investigating the impact of each enantiomer of ML-SA1 on the TRPML1-TFEB axis. Our findings revealed that (S)-ML-SA1 acts as an agonist for TRPML1 at the lysosomal membrane. This activation prompts transcription factor EB (TFEB) to translocate from the cytosol to the nucleus in a dose-dependent manner within live cells. Consequently, this signaling pathway enhances the expression of coordinated lysosomal expression and regulation (CLEAR) genes and activates autophagic flux. Our study presents evidence for the potential use of (S)-ML-SA1 in the development of new therapies for lysosomal storage diseases that target TRPML1. (AU) | |
| FAPESP's process: | 20/02006-0 - Molecular and structural characterization of RNA binding proteins acting as potential disease targets in cancer and neurology |
| Grantee: | Katlin Brauer Massirer |
| Support Opportunities: | Research Grants - Research Partnership for Technological Innovation - PITE |
| FAPESP's process: | 21/04853-4 - Study of the therapeutic potential of new modulators of the lysosomal calcium channel hTRPML1 |
| Grantee: | Micael Rodrigues Cunha |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem) |
| Grantee: | Katlin Brauer Massirer |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 19/22319-5 - Vibrational circular dichroism spectral markers: facilitating absolute configuration assignment of natural products |
| Grantee: | João Marcos Batista Junior |
| Support Opportunities: | Regular Research Grants |