title: Targeting Protein-Protein Interactions in the HIF System.
abstract: Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF α-subunits, which 1) signal for degradation of HIF-α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF-mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein-protein and protein-nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein-protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. sarah.wilkins@chem.ox.ac.uk.
authors.forename: Sarah E
authors.identifier: http://orcid.org/0000-0003-1347-3328
authors.initials: SE
authors.lastname: Wilkins
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
authors.forename: Martine I
authors.identifier: http://orcid.org/0000-0003-2141-5988
authors.initials: MI
authors.lastname: Abboud
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
authors.forename: Rebecca L
authors.identifier: http://orcid.org/0000-0003-4039-9311
authors.initials: RL
authors.lastname: Hancock
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
authors.forename: Christopher J
authors.identifier: http://orcid.org/0000-0002-0290-6565
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D000818:Animals; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000378:metabolism*; D009696:Nucleic Acids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D000072258:Tumor Hypoxia / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009696:Nucleic Acids
keywords: HIF; hydroxylation; hypoxia; inhibitors; oxygenases; protein-protein interactions