The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity.

Abstract

A mismatch between β-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington's disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.

• Authors: Francesca Di Cristo, Anna Calarco, Filomena Anna Digilio, Maria Stefania Sinicropi, Camillo Rosano, Umberto Galderisi, Mariarosa Anna Beatrice Melone, Carmela Saturnino, Gianfranco Peluso
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 19 (Oct 08 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33050117 (Publication Type: Journal Article)

Chemical References

• Methylhydrazines
• SLC22A5 protein, human
• Solute Carrier Family 22 Member 5
• 3-(2,2,2-trimethylhydrazine)propionate
• Carnitine

Topics

• Animals
• Carnitine (metabolism)
• Cell Line
• Cell Survival (drug effects)
• Disease Models, Animal
• Drosophila melanogaster (drug effects, genetics)
• Drug Evaluation, Preclinical (methods)
• Humans
• Huntington Disease (drug therapy, metabolism)
• Longevity (drug effects)
• Methylhydrazines (pharmacology)
• Mice
• Molecular Docking Simulation
• Protein Aggregation, Pathological (drug therapy)
• Signal Transduction (drug effects)
• Solute Carrier Family 22 Member 5 (antagonists & inhibitors, genetics, metabolism)
• Transfection
• Treatment Outcome