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