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Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor


Günter, Julia; Wenger, Roland H; Scholz, Carsten C (2020). Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor. Journal of Photochemistry and Photobiology B: Biology, 210:111980.

Abstract

The three hypoxia-inducible factor (HIF) prolyl-4-hydroxylase domain (PHD) 1–3 enzymes confer oxygen sensitivity
to the HIF pathway and are novel therapeutic targets for treatment of renal anemia. Inhibition of the
PHDs may further be beneficial in other hypoxia-associated diseases, including ischemia and chronic inflammation.
Several pharmacologic PHD inhibitors (PHIs) are available, but our understanding of their selectivity
and its chemical basis is limited. We here report that the PHI JNJ-42041935 (JNJ-1935) is structurally
similar to the firefly luciferase substrate D-luciferin. Our results demonstrate that JNJ-1935 is a novel inhibitor
of firefly luciferase enzymatic activity. In contrast, the PHIs FG-4592 (roxadustat) and FG-2216 (ICA, BIQ, IOX3,
YM 311) did not affect firefly luciferase. The JNJ-1935 mode of inhibition is competitive with a Ki of 1.36 μM. Dluciferin
did not inhibit the PHDs, despite its structural similarity to JNJ-1935. This study provides insights into
a previously unknown JNJ-1935 off-target effect as well as into the chemical requirements for firefly luciferase
and PHD inhibitors and may inform the development of novel compounds targeting these enzymes.

Abstract

The three hypoxia-inducible factor (HIF) prolyl-4-hydroxylase domain (PHD) 1–3 enzymes confer oxygen sensitivity
to the HIF pathway and are novel therapeutic targets for treatment of renal anemia. Inhibition of the
PHDs may further be beneficial in other hypoxia-associated diseases, including ischemia and chronic inflammation.
Several pharmacologic PHD inhibitors (PHIs) are available, but our understanding of their selectivity
and its chemical basis is limited. We here report that the PHI JNJ-42041935 (JNJ-1935) is structurally
similar to the firefly luciferase substrate D-luciferin. Our results demonstrate that JNJ-1935 is a novel inhibitor
of firefly luciferase enzymatic activity. In contrast, the PHIs FG-4592 (roxadustat) and FG-2216 (ICA, BIQ, IOX3,
YM 311) did not affect firefly luciferase. The JNJ-1935 mode of inhibition is competitive with a Ki of 1.36 μM. Dluciferin
did not inhibit the PHDs, despite its structural similarity to JNJ-1935. This study provides insights into
a previously unknown JNJ-1935 off-target effect as well as into the chemical requirements for firefly luciferase
and PHD inhibitors and may inform the development of novel compounds targeting these enzymes.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Biophysics, Radiological and Ultrasound Technology, Radiation, Radiology Nuclear Medicine and imaging
Language:English
Date:1 September 2020
Deposited On:07 Aug 2020 09:30
Last Modified:07 Aug 2020 09:51
Publisher:Elsevier
ISSN:1011-1344
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1016/j.jphotobiol.2020.111980
Project Information:
  • : FunderSNSF
  • : Grant ID310030_184813
  • : Project TitleSingle cell variability of hypoxia-inducible gene expression
  • : FunderJunior Grant of the NCCR Kidney.CH
  • : Grant ID
  • : Project Title

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