title: A novel MitoNEET ligand, TT01001, improves diabetes and ameliorates mitochondrial function in db/db mice.
abstract: The mitochondrial outer membrane protein mitoNEET is a binding protein of the insulin sensitizer pioglitazone (5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) and is considered a novel target for the treatment of type II diabetes. Several small-molecule compounds have been identified as mitoNEET ligands using structure-based design or virtual docking studies. However, there are no reports about their therapeutic potential in animal models. Recently, we synthesized a novel small molecule, TT01001 [ethyl-4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate], designed on the basis of pioglitazone structure. In this study, we assessed the pharmacological properties of TT01001 in both in vitro and in vivo studies. We found that TT01001 bound to mitoNEET without peroxisome proliferator-activated receptor-γ activation effect. In type II diabetes model db/db mice, TT01001 improved hyperglycemia, hyperlipidemia, and glucose intolerance, and its efficacy was equivalent to that of pioglitazone, without the pioglitazone-associated weight gain. Mitochondrial complex II + III activity of the skeletal muscle was significantly increased in db/db mice. We found that TT01001 significantly suppressed the elevated activity of the complex II + III. These results suggest that TT01001 improved type II diabetes without causing weight gain and ameliorated mitochondrial function of db/db mice. This is the first study that demonstrates the effects of a mitoNEET ligand on glucose metabolism and mitochondrial function in an animal disease model. These findings support targeting mitoNEET as a potential therapeutic approach for the treatment of type II diabetes.
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.) Takehiro_Takahashi@nts.toray.co.jp.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Amikura
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Kozue
authors.initials: K
authors.lastname: Kato
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Serizawa
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Kanako
authors.initials: K
authors.lastname: Serizawa
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Akazawa
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Takumi
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Koji
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Emi
authors.initials: E
authors.lastname: Ogasawara
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hayashi
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.affiliation: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan (T.T., M.Y., K.A., Koz.K., T.S., K.S., D.A., T.A., Koj.K., M.K.); and Faculty of Life and Environmental Science, University of Tsukuba, Tsukuba, Ibaraki, Japan (E.O., J.-I.H., K.N.).
authors.forename: Mie
authors.initials: M
authors.lastname: Kainoh
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004272:DNA, Mitochondrial / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004926:Escherichia coli / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D033862:Iron-Binding Proteins / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008815:Mice, Inbred Strains; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020349:Surface Plasmon Resonance; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; C525595:CISD1 protein, human; D004272:DNA, Mitochondrial; D007004:Hypoglycemic Agents; D033862:Iron-Binding Proteins; D008024:Ligands; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D010880:Piperidines; C000596179:ethyl 4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate; C519501:mitoNEET protein, mouse; D013890:Thiourea