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

1
Elleva Pharma S.R.L., via Pietro Castellino 111, 80131 Naples, Italy
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Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy
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Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy
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Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Vico Luigi De Crecchio 1, 80138 Naples, Italy
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Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania “Luigi Vanvitelli”, via Sergio Pansini 5, 80131 Naples, Italy
7
Department of Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy
*
Authors to whom correspondence should be addressed.
This author contributed to this work as senior author.
Int. J. Mol. Sci. 2020, 21(19), 7431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197431
Received: 30 September 2020 / Accepted: 6 October 2020 / Published: 8 October 2020
(This article belongs to the Section Molecular Biology)
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. View Full-Text
Keywords: carnitine system; carnitine/organic cation transporter (OCTN2); mitochondrial β-oxidation; Huntington’s disease (HD); meldonium carnitine system; carnitine/organic cation transporter (OCTN2); mitochondrial β-oxidation; Huntington’s disease (HD); meldonium
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MDPI and ACS Style

Di Cristo, F.; Calarco, A.; Digilio, F.A.; Sinicropi, M.S.; Rosano, C.; Galderisi, U.; Melone, M.A.B.; Saturnino, C.; Peluso, G. The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity. Int. J. Mol. Sci. 2020, 21, 7431. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197431

AMA Style

Di Cristo F, Calarco A, Digilio FA, Sinicropi MS, Rosano C, Galderisi U, Melone MAB, Saturnino C, Peluso G. The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity. International Journal of Molecular Sciences. 2020; 21(19):7431. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197431

Chicago/Turabian Style

Di Cristo, Francesca, Anna Calarco, Filomena A. Digilio, Maria S. Sinicropi, Camillo Rosano, Umberto Galderisi, Mariarosa A.B. Melone, Carmela Saturnino, and Gianfranco Peluso. 2020. "The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity" International Journal of Molecular Sciences 21, no. 19: 7431. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197431

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