Repurposing of glycine transport inhibitors for the treatment of erythropoietic protoporphyria

François Halloy, Pavithra S. Iyer, Alice Ghidini, Veronika Lysenko, Jasmin Barman-Aksözen, Chia Pei Grubenmann, Jessica Jucker, Nicole Wildner-Verhey van Wijk, Marc David Ruepp, Elisabeth I. Minder, Anna Elisabeth Minder, Xiaoye Schneider-Yin, Alexandre P.A. Theocharides, Daniel Schümperli*, Jonathan Hall

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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 K56211B4 cells, and in primary erythroid cultures from an EPP patient. Our findings open the door to investigation of glycine transport inhibitors for HBS disorders.

Original languageEnglish
Pages (from-to)1221-1234.e6
JournalCell Chemical Biology
Volume28
Issue number8
DOIs
Publication statusPublished - 19 Aug 2021

Keywords

  • CRISPR-Cas9
  • drug repurposing
  • erythropoietic protoporphyria
  • glycine transporter 2
  • oxidative stress
  • photodamage
  • protoporphyrin IX

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