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A Simple Method for High Throughput Chemical Screening in Caenorhabditis Elegans
Published on: March 20, 2018
Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
Chensu Wang1,2, Hanspeter Niederstrasser3, Peter M Douglas4
1Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
Abstract:
Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.
Insights
Researchers discovered novel small molecules that activate transcription factor EB (TFEB), mimicking starvation effects. These TFEB activators, formulated in nanoparticles, show promise for treating metabolic disorders and aging.
Area of Science:
- Biochemistry
- Cell Biology
- Nanotechnology
Background:
- Starvation and caloric restriction activate transcription factor EB (TFEB), a key regulator of lipid metabolism and lysosomal function.
- TFEB activation is a promising therapeutic strategy for metabolic disorders like obesity and liver steatosis, as well as aging.
Purpose of the Study:
- To identify small-molecule agonists of TFEB using a nanotechnology-enabled high-throughput screen.
- To investigate the therapeutic potential of novel TFEB activators for metabolic and age-related diseases.
Main Methods:
- High-throughput screening using nanotechnology to identify TFEB agonists.
- Mode of action studies to elucidate Ca2+-dependent mechanisms of TFEB activation.
- Formulation of lead compounds in liver-tropic nanoparticles for in vivo studies.
Main Results:
- Identified three novel small-molecule TFEB agonists: digoxin, ikarugamycin, and alexidine dihydrochloride.
- Discovered distinct Ca2+-dependent mechanisms for TFEB activation by these compounds.
- Nanoparticle formulations demonstrated hepatoprotection against steatosis in mice and extended lifespan in C. elegans.
Conclusions:
- Small-molecule TFEB activators represent a promising therapeutic avenue for metabolic and age-related disorders.
- Nanotechnology-based drug delivery enhances the therapeutic efficacy of TFEB activators.
