{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T08:33:52Z","timestamp":1769502832426,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Miur - Regione Campania","award":["POR Campania FESR 2014_2020"],"award-info":[{"award-number":["POR Campania FESR 2014_2020"]}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PON 03 PE_00110_1\/ptd1_000410"],"award-info":[{"award-number":["PON 03 PE_00110_1\/ptd1_000410"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A mismatch between \u03b2-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\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms21197431","type":"journal-article","created":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T10:19:23Z","timestamp":1602238763000},"page":"7431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity"],"prefix":"10.3390","volume":"21","author":[{"given":"Francesca","family":"Di Cristo","sequence":"first","affiliation":[{"name":"Elleva Pharma S.R.L., via Pietro Castellino 111, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1441-7662","authenticated-orcid":false,"given":"Anna","family":"Calarco","sequence":"additional","affiliation":[{"name":"Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-3760","authenticated-orcid":false,"given":"Filomena Anna","family":"Digilio","sequence":"additional","affiliation":[{"name":"Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2435-8931","authenticated-orcid":false,"given":"Maria Stefania","family":"Sinicropi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2949-9215","authenticated-orcid":false,"given":"Camillo","family":"Rosano","sequence":"additional","affiliation":[{"name":"Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umberto","family":"Galderisi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Vico Luigi De Crecchio 1, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7213-9277","authenticated-orcid":false,"given":"Mariarosa Anna Beatrice","family":"Melone","sequence":"additional","affiliation":[{"name":"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 \u201cLuigi Vanvitelli\u201d, via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7419-8780","authenticated-orcid":false,"given":"Carmela","family":"Saturnino","sequence":"additional","affiliation":[{"name":"Department of Science, University of Basilicata, Viale dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianfranco","family":"Peluso","sequence":"additional","affiliation":[{"name":"Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6030","DOI":"10.1038\/onc.2017.216","article-title":"Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: Molecular basis and pathophysiological consequences","volume":"36","author":"Valentino","year":"2017","journal-title":"Oncogene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fcvm.2018.00068","article-title":"Loss of Metabolic Flexibility in the Failing Heart","volume":"5","author":"Karwi","year":"2018","journal-title":"Front Cardiovasc. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/s41419-018-0313-7","article-title":"The carnitine system and cancer metabolic plasticity","volume":"9","author":"Melone","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0006-2952(88)90717-4","article-title":"3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties","volume":"37","author":"Simkhovich","year":"1988","journal-title":"Biochem. Pharmacol."},{"key":"ref_5","first-page":"85","article-title":"Topographic and quantitative characteristics of adipose tissue in various aborigines of Siberia (women)","volume":"97","author":"Zhvavyi","year":"1989","journal-title":"Arkh. Anat. Gistol. Embriol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1111\/j.1476-5381.2009.00319.x","article-title":"Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats","volume":"157","author":"Liepinsh","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.lfs.2008.08.008","article-title":"Mildronate decreases carnitine availability and up-regulates glucose uptake and related gene expression in the mouse heart","volume":"83","author":"Liepinsh","year":"2008","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1742-7843.2009.00461.x","article-title":"Effects of long-term mildronate treatment on cardiac and liver functions in rats","volume":"105","author":"Liepinsh","year":"2009","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9233","DOI":"10.1002\/jcp.27602","article-title":"Meldonium improves Huntington\u2019s disease mitochondrial dysfunction by restoring peroxisome proliferator-activated receptor gamma coactivator 1alpha expression","volume":"234","author":"Finicelli","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.prostaglandins.2016.07.004","article-title":"PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid","volume":"125","author":"Singh","year":"2016","journal-title":"Prostaglandins Other Lipid. Mediat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1046\/j.1432-1327.2001.02065.x","article-title":"Development and characterization of an animal model of carnitine deficiency","volume":"268","author":"Spaniol","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1248\/bpb.23.770","article-title":"Effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on tissue carnitine and lipid levels in rats","volume":"23","author":"Hayashi","year":"2000","journal-title":"Biol. Pharm. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13036","DOI":"10.1038\/s41598-018-31484-5","article-title":"Whole grain intake associated molecule 5-aminovaleric acid betaine decreases beta-oxidation of fatty acids in mouse cardiomyocytes","volume":"8","author":"Karkkainen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cmet.2006.10.004","article-title":"Thermoregulatory and metabolic defects in Huntington\u2019s disease transgenic mice implicate PGC-1alpha in Huntington\u2019s disease neurodegeneration","volume":"4","author":"Weydt","year":"2006","journal-title":"Cell. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2174\/1389450053344975","article-title":"Huntington\u2019s disease: New frontiers for molecular and cell therapy","volume":"6","author":"Melone","year":"2005","journal-title":"Curr. Drug Targets"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.bbadis.2012.09.001","article-title":"Mutant huntingtin regulates EGF receptor fate in non-neuronal cells lacking wild-type protein","volume":"1832","author":"Melone","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1161\/CIRCULATIONAHA.105.586107","article-title":"Uptake of cardiovascular drugs into the human heart: Expression, regulation, and function of the carnitine transporter OCTN2 (SLC22A5)","volume":"113","author":"Grube","year":"2006","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.phrs.2016.01.019","article-title":"Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity","volume":"113","author":"Dambrova","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1096\/fj.12-219220","article-title":"A novel human embryonic stem cell-derived Huntington\u2019s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration","volume":"27","author":"Lu","year":"2013","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34916","DOI":"10.1038\/srep34916","article-title":"Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington\u2019s disease model system","volume":"6","author":"Xi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1038\/cr.2017.113","article-title":"Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington\u2019s disease models","volume":"27","author":"Yu","year":"2017","journal-title":"Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Choi, J.Y., Jang, H.M., Park, J., Kim, Y.S., Kang, S.W., Yang, C.W., Kim, N.H., Cho, J.H., Park, S.H., and Kim, C.D. (2013). Clinical Research Center for End Stage Renal Disease, I., Survival advantage of peritoneal dialysis relative to hemodialysis in the early period of incident dialysis patients: A nationwide prospective propensity-matched study in Korea. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084257"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/hmg\/ddt406","article-title":"Loss of caveolin-1 expression in knock-in mouse model of Huntington\u2019s disease suppresses pathophysiology in vivo","volume":"23","author":"Trushina","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1128\/MCB.01027-07","article-title":"Regulation of the Drosophila hypoxia-inducible factor alpha Sima by CRM1-dependent nuclear export","volume":"28","author":"Romero","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"32492","DOI":"10.1074\/jbc.M805832200","article-title":"Overexpression of glucose-6-phosphate dehydrogenase extends the life span of Drosophila melanogaster","volume":"283","author":"Legan","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Besson, M.T., Alegria, K., Garrido-Gerter, P., Barros, L.F., and Lievens, J.C. (2015). Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118765"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0140-6736(63)91500-9","article-title":"The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus","volume":"1","author":"Randle","year":"1963","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1194\/jlr.RA119000177","article-title":"Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation","volume":"61","author":"Lundsgaard","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1124\/dmd.108.023929","article-title":"The carnitine transporter SLC22A5 is not a general drug transporter, but it efficiently translocates mildronate","volume":"37","author":"Grigat","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1177\/2472555218812821","article-title":"OCTN: A Small Transporter Subfamily with Great Relevance to Human Pathophysiology, Drug Discovery, and Diagnostics","volume":"24","author":"Pochini","year":"2019","journal-title":"SLAS Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.cmet.2019.03.004","article-title":"Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice","volume":"29","author":"Polyzos","year":"2019","journal-title":"Cell. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.freeradbiomed.2018.10.446","article-title":"Mitochondrial superoxide generation induces a parkinsonian phenotype in zebrafish and huntingtin aggregation in human cells","volume":"130","author":"Pinho","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"440","DOI":"10.4103\/1673-5374.128258","article-title":"Examination of Huntington\u2019s disease in a Chinese family","volume":"9","author":"Yu","year":"2014","journal-title":"Neural Regen. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6","article-title":"Automated docking of flexible ligands: Applications of AutoDock","volume":"9","author":"Goodsell","year":"1996","journal-title":"J. Mol. Recognit."},{"key":"#cr-split#-ref_36.1","unstructured":"Altman, R.B., Lauderdale, K., Dunker, A.K., Hunter, L., and Klein, T.E. (1999). Integrating computation and visualization for biomolecular analysis: An example using python and AVS. Biocomputing '99, Proceedings of the"},{"key":"#cr-split#-ref_36.2","unstructured":"Pacific Symposium on Biocomputing, Mauna Lani, HI, USA, 4-9 January 1999, World Scientific Publishing."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"50514","DOI":"10.1074\/jbc.M309348200","article-title":"Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-d-aspartate receptor activation in Huntington\u2019s disease knock-in striatal cells","volume":"278","author":"Gines","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0005-2736(01)00328-5","article-title":"Na(+)-coupled transport of l-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney","volume":"1512","author":"Tamai","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1021\/jm401603e","article-title":"Targeting carnitine biosynthesis: Discovery of new inhibitors against gamma-butyrobetaine hydroxylase","volume":"57","author":"Tars","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.1016\/S0021-9258(18)62901-1","article-title":"Cofactor requirements of gamma-butyrobetaine hydroxylase from rat liver","volume":"245","author":"Lindstedt","year":"1970","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.chembiol.2010.09.016","article-title":"Structural and mechanistic studies on gamma-butyrobetaine hydroxylase","volume":"17","author":"Leung","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/dev.118.2.401","article-title":"Targeted gene expression as a means of altering cell fates and generating dominant phenotypes","volume":"118","author":"Brand","year":"1993","journal-title":"Development"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bovier, T.F., Cavaliere, D., Colombo, M., Peluso, G., Giordano, E., and Digilio, F.A. (2019). Methods to Test Endocrine Disruption in Drosophila melanogaster. J. Vis. Exp., e59535.","DOI":"10.3791\/59535-v"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5427","DOI":"10.1073\/pnas.1516217112","article-title":"Transcellular spreading of huntingtin aggregates in the Drosophila brain","volume":"112","author":"Babcock","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/nn.3761","article-title":"Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons","volume":"17","author":"Rieker","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.molcel.2018.07.032","article-title":"mHTT Seeding Activity: A Marker of Disease Progression and Neurotoxicity in Models of Huntington\u2019s Disease","volume":"71","author":"Ast","year":"2018","journal-title":"Mol. Cell."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"36","DOI":"10.5607\/en.2014.23.1.36","article-title":"Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington\u2019s Disease","volume":"23","author":"Kim","year":"2014","journal-title":"Exp. Neurobiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7431\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:17:42Z","timestamp":1760177862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/19\/7431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,8]]},"references-count":49,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21197431"],"URL":"https:\/\/doi.org\/10.3390\/ijms21197431","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,8]]}}}