Isis Innovation Limited

Oxford Biomedica (uk) Limited

Oxford University Innovation Ltd

Christopher William Pugh

Peter John Ratcliffe

Christopher Joseph Schofield

Patrick Henry Maxwell

Adrian Llewllyn Harris

John David Firth

Ian James Stratford

Luke McNeill

Kirsty Sarah Hewitson

Jonathan Mark Elkins

Jonathan Mark Gleadle

A novel class of hydroxylases is described having the amino acid sequence of SEQ ID NO: 2, 4, 6 and 8, and variants and fragments thereof having HIF hydroxylation activity. The polypeptides of the invention have in particular prolyl hydroxylase activity. An assay method monitors the interaction of the HIF hydroxylase with a substrate. Modulators of HIF hydroxylase are provided for use in the treatment of a condition associated with increased or decreased HIF levels or activity or for the treatment of a condition where it is desirable to modulate HIF levels or activity.

Antibody against human HIF hydroxylase

Assay for identifying a modulator of HIF hydroxylase

A method of identifying, screening, characterising or designing a chemical entity, which mimics or binds to FIH, is described. The method comprises comparing a structural model of FIH with a structural model for said chemical entity, wherein said structural model of FIH is derived from structural factors or structural coordinates determined by subjecting to X-ray diffraction measurements a crystal comprising FIH. Such chemical entities may be used in the treatment of a condition associated with increased or decreased HIF levels or activity.

Method of identifying a chemical entity which is a hydroxylase modulator

The invention relates to the finding that the VHL tumour suppressor protein regulates hypoxia inducible factor &#x3b1; subunits, by targeting HIF &#x3b1; for destruction in normoxic, but not hypoxic cells. The invention provides assays for modulators of this interaction, and peptides based upon HIF &#x3b1; subunit sequences which may modulate this interaction.

Interaction between the VHL tumor suppressor and hypoxia inducible factor, and assay methods relating thereto

The invention provides a compound of one of the formulae (A), (B), (C), (D), (E), (F) as herein defined, or a salt thereof, for use in the treatment of a condition associated with increased or decreased HIF levels or activity, or a condition in which an increase or decrease in HIF levels or activity may be beneficial. 

HIF hydroxylase inhibitors

A method of identifying an agent which modulates hydroxylation of hypoxia inducible factor (HIF), comprises contacting a HIF asparagine hydroxylase and a test substance in the presence of a substrate of the hydroxylase under conditions in which asparagine in the substrate is hydroxylated in the absence of the test substance; and determining hydroxylation of the substrate. Preferably the substrate is a HIF polypeptide comprising HIF-1&#x3b1;, a fragment thereof comprising Asn 803 of HIF-1&#x3b1; or a peptide analogue of HIF-1&#x3b1; or fragment thereof comprising an asparagine equivalent to Asn 803 of HIF-1&#x3b1; and wherein hydroxylation of Asn 803 or of a said equivalent asparagine is determined.

Assays for modulators of asparaginyl hydroxylase

The invention relates to the finding that the VHL tumour suppressor protein regulates hypoxia inducible factor &agr; subunits, by targeting HIF &agr; for destruction in normoxic, but not hypoxic cells. The invention provides assays for modulators of this interaction, and peptides based upon HIF &agr; subunit sequence which may modulate this interaction.

Nucleic acid constructs comprising hypoxia response elements in operable linkage with a coding sequence of a gene of interest, and methods for expressing a nucleic acid sequence using the constructs, are disclosed. In particular, such nucleic acid constructs comprise genes encoding prodrug activation systems or cytokines.

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Oxford, United Kingdom

Christopher William Pugh