Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor

Autor: Roland H. Wenger, Julia Günter, Carsten C. Scholz
Přispěvatelé: University of Zurich, Scholz, Carsten C
Rok vydání: 2020
Předmět:
Renilla
Structural similarity
Biophysics
Glycine
610 Medicine & health
Inflammation
Binding
Competitive
10052 Institute of Physiology
03 medical and health sciences
0302 clinical medicine
Dioxygenase
Luciferases
Firefly
medicine
2741 Radiology
Nuclear Medicine and Imaging
Animals
Radiology
Nuclear Medicine and imaging
Luciferase
Epigenetics
Benzothiazoles
3614 Radiological and Ultrasound Technology
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Radiation
Radiological and Ultrasound Technology
Fireflies
Prolyl-Hydroxylase Inhibitors
HIF prolyl-hydroxylase inhibitor
Isoquinolines
Recombinant Proteins
3. Good health
3108 Radiation
Kinetics
Enzyme
chemistry
Biochemistry
Radiology Nuclear Medicine and imaging
Erythropoietin
030220 oncology & carcinogenesis
570 Life sciences
biology
medicine.symptom
1304 Biophysics
medicine.drug
Zdroj: Journal of photochemistry and photobiology. B, Biology. 210
ISSN: 1873-2682
Popis: 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. D-luciferin 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.
Databáze: OpenAIRE
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