Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress.

Autor:	Sonoda K; Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.; Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan.; The United Graduate School of Agricultural Sciences, Kagoshima University 1-21-24 Korimoto, Kagoshima 890-0065, Japan., Bogahawatta S; Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.; Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan.; The United Graduate School of Agricultural Sciences, Kagoshima University 1-21-24 Korimoto, Kagoshima 890-0065, Japan., Katayama A; Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan., Ujike S; Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan., Kuroki S; Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan., Kitagawa N; Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan., Hirotsuru K; Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan., Suzuki N; Division of Oxygen Biology, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8575, Japan., Miyata T; Department of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan., Kawaguchi SI; Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan.; The United Graduate School of Agricultural Sciences, Kagoshima University 1-21-24 Korimoto, Kagoshima 890-0065, Japan., Tsujita T; Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan.; The United Graduate School of Agricultural Sciences, Kagoshima University 1-21-24 Korimoto, Kagoshima 890-0065, Japan.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2022 Apr 13; Vol. 5 (5), pp. 362-372. Date of Electronic Publication: 2022 Apr 13 (Print Publication: 2022).
DOI:	10.1021/acsptsci.2c00002
Abstrakt:	Hypoxia-inducible factor-α (HIF-α) activation has shown promising results in the treatment of ischemia, such as stroke, myocardial infarction, and chronic kidney disease. A number of HIF-α activators have been developed to improve the symptoms of these diseases. Many feature 2-oxoglutarate (2-OG) scaffolds that interact with the active centers of prolyl hydroxylase domain-containing proteins (PHDs), displacing the coenzyme 2-OG. This stabilizes HIF-α. Therefore, the specificity of the 2-OG analogs is not high. Here, we identified 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid (PyrzA) among over 10 000 compounds as a novel HIF activator that does not contain a 2-OG scaffold. In cultured cells, PyrzA enhanced HIF-α stability and upregulated the expression of HIF target genes. Interestingly, PyrzA decreased HIF-1α prolyl hydroxylation, suggesting that PyrzA may activate HIF to prevent the degradation of HIF-α. These results indicate that PyrzA stabilizes HIF via a novel mechanism and could be a potential HIF activator candidate. Competing Interests: The authors declare the following competing financial interest(s): S-i.K. and T.T. are advisory members for Tetra Create Co., Ltd. All other authors declare no conflicts of interest. (© 2022 American Chemical Society.)
Databáze:	MEDLINE
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