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Repurposing of glycine transport inhibitors for the treatment of erythropoietic protoporphyria.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2021 Aug 19; Vol. 28 (8), pp. 1221-1234.e6. Date of Electronic Publication: 2021 Mar 22. - Publication Year :
- 2021
-
Abstract
- Erythropoietic protoporphyria (EPP) is a rare disease in which patients experience severe light sensitivity. It is caused by a deficiency of ferrochelatase (FECH), the last enzyme in heme biosynthesis (HBS). The lack of FECH causes accumulation of its photoreactive substrate protoporphyrin IX (PPIX) in patients' erythrocytes. Here, we explored an approach for the treatment of EPP by decreasing PPIX synthesis using small-molecule inhibitors directed to factors in the HBS pathway. We generated a FECH-knockout clone from K562 erythroleukemia cells, which accumulates PPIX and undergoes oxidative stress upon light exposure. We used these matched cell lines to screen a set of publicly available inhibitors of factors in the HBS pathway. Inhibitors of the glycine transporters GlyT1 and GlyT2 lowered levels of PPIX and markers of oxidative stress selectively in K562 <superscript>11B4</superscript> cells, and in primary erythroid cultures from an EPP patient. Our findings open the door to investigation of glycine transport inhibitors for HBS disorders.<br />Competing Interests: Declaration of interests J.B.A. is a founding member and vice president of the International Porphyria Patient Network, a not-for-profit patient organization. A.M. received funding from Clinuvel Pharmaceuticals for research on EPP.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Cells, Cultured
Erythrocytes drug effects
Erythrocytes metabolism
Glycine Plasma Membrane Transport Proteins metabolism
Humans
K562 Cells
Molecular Structure
Protoporphyria, Erythropoietic metabolism
Glycine Plasma Membrane Transport Proteins antagonists & inhibitors
Protoporphyria, Erythropoietic drug therapy
Protoporphyrins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 28
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 33756123
- Full Text :
- https://doi.org/10.1016/j.chembiol.2021.02.021