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Inhibition of a viral prolyl hydroxylase
Affiliation:1. E.I. Du Pont de Nemours and Company, Stine Haskell Research Center, 1090 Elkton Rd., Newark, DE 19711, USA;2. School of Behavioral and Brain Sciences, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, USA;3. University of Arizona, Department of Pharmacology, 1501 N. Campbell Ave., Tucson, AZ 85724, USA;1. Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain;2. Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain;3. Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040, Madrid, Spain;4. Instituto de Investigaciones Biomédicas “Alberto Sols”, (IIB-CSIC), C/Arturo Duperier 4, 28029, Madrid, Spain;5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031, Madrid, Spain;1. University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia;2. Blood Transfusion Center of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia;3. Jožef Stefan Institute, Department of Biotechnology, Jamova 39, 1000 Ljubljana, Slovenia;4. Univ. Grenoble Alpes, Institut de Biologie Structurale (IBS), F-38000 Grenoble, France;5. CNRS, IBS, F-38000 Grenoble, France;6. CEA, IBS, F-38027 Grenoble, France;1. Institute of Biosciences, Chemistry and Physics Faculty, TU Bergakademie Freiberg, 09599 Freiberg, Germany;2. Microbial Biotechnology, Faculty of Biology and Biotechnology, Ruhr-Universität Bochum, 44780 Bochum, Germany;1. Systems Biology Ireland, University College Dublin, Dublin 4, Ireland;2. Conway Institute, University College Dublin, Dublin 4, Ireland;3. Ludwig Institute for Cancer Research Ltd., SE-17177 Stockholm, Sweden;4. Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden;5. Cancer Research UK Edinburgh Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK;1. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan;2. Nippon Pharmaceutical Chemicals Co., Ltd., 2-8-18 Higashiosaka-shi, Osaka 577-0056, Japan;3. CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Abstract:The hydroxylation of prolyl-residues in eukaryotes is important in collagen biosynthesis and in hypoxic signalling. The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are drug targets for the treatment of anaemia, while the procollagen prolyl hydroxylases and other 2-oxoglutarate dependent oxygenases are potential therapeutic targets for treatment of cancer, fibrotic disease, and infection. We describe assay development and inhibition studies for a procollagen prolyl hydroxylase from Paramecium bursaria chlorella virus 1 (vCPH). The results reveal HIF PHD inhibitors in clinical trials also inhibit vCPH. Implications for the targeting of the human PHDs and microbial prolyl hydroxylases are discussed.
Keywords:Prolyl hydroxylase inhibitor  2-Oxoglutarate  α-Ketoglutarate oxygenase  Collagen biosynthesis  Hypoxia inducible factor  Erythropoietin (EPO)
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