Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Montalbetti, Nicolas; Simonin, Alexandre; Simonin, Céline; Awale, Mahendra; Reymond, Jean-Louis; Hediger, Matthias (2015). Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2. Biochemical pharmacology, 96(3), pp. 216-224. Elsevier 10.1016/j.bcp.2015.05.002

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Divalent metal transporter-1 (SLC11A2/DMT1) uses the H+ electrochemical gradient as the driving force to transport divalent metal ions such as Fe2+, Mn2+ and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H+-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H+-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20 μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Montalbetti, Nicolas; Simonin, Alexandre; Simonin, Céline; Awale, Mahendra; Reymond, Jean-Louis and Hediger, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

22 Jan 2016 15:03

Last Modified:

12 Sep 2016 13:18

Publisher DOI:

10.1016/j.bcp.2015.05.002

PubMed ID:

26047847

BORIS DOI:

10.7892/boris.74729

URI:

https://boris.unibe.ch/id/eprint/74729

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