Inhibition of a viral prolyl hydroxylase

Bioorg Med Chem. 2019 Jun 15;27(12):2405-2412. doi: 10.1016/j.bmc.2019.01.018. Epub 2019 Jan 23.

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: 2-Oxoglutarate; Collagen biosynthesis; Erythropoietin (EPO); Hypoxia inducible factor; Prolyl hydroxylase inhibitor; α-Ketoglutarate oxygenase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Assays
  • Hydroxylation
  • Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
  • Ketoglutaric Acids / chemistry
  • Oligopeptides / chemistry
  • Phycodnaviridae / enzymology
  • Procollagen-Proline Dioxygenase / chemistry*
  • Prolyl-Hydroxylase Inhibitors / chemistry*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Ketoglutaric Acids
  • Oligopeptides
  • Prolyl-Hydroxylase Inhibitors
  • Procollagen-Proline Dioxygenase
  • Hypoxia-Inducible Factor-Proline Dioxygenases

Supplementary concepts

  • Paramecium bursaria Chlorella virus 1