Nonhuman pregnane x receptor sequences for use in comparative pharmacology
OwnerSteven Anthony Kliewer, Jodi Marie Maglich +3inventors
InventorsSteven Anthony Kliewer, Jodi Marie Maglich, John Tomlin Moore, Linda Becker Moore, Timothy Mark Willson
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Abstract
Polynucleotides and polypeptides of canine, primate, porcine and fish pregnane X receptor (PXR), as well as expression vectors and host cells for expression of these PXR receptors, are provided. Also provided are methods for screening for modulators of these PXR receptors and using these receptors for comparative pharmacology and in selection of appropriate preclinical animal models predictive of human PXR activity.
Claims19
An isolated pregnane X nuclear receptor polypeptide comprising:
- (a) an amino acid sequence of SEQ ID NO:
- 2, 4, 6 or 8;
- (b) a variant of the amino acid sequence as defined in (a) which modulates P450 3A4 levels or activity;
- or
- (c) a fragment of (a) or (b) which modulates P450 3A4 levels or activity.
A polynucleotide encoding a pregnane X receptor polypeptide which modulates P450 3A4 levels or activity, said polynucleotide comprising:
- (a) a nucleic acid sequence of SEQ ID NO:
- 1, 3, 5 or 7;
- (b) a nucleic acid sequence which hybridizes under stringent conditions to the nucleic acid sequence as defined in (a);
- (c) a nucleic acid sequence that is degenerate as a result of the genetic code to the nucleic acid sequence as defined in (a) or (b);
- or
- (d) a nucleic acid sequence having at least 60% identity to the nucleic acid sequence as defined in (a), (b) or (c).
A method for the identification of a compound that modulates pregnane X receptor activity and/or expression, said method comprising:
- (a) contacting a test compound with a canine, porcine, primate or Zebrafish pregnane X recpetor polypeptide or polynucleotide;
- and
- (b) determining an effect of the test compound on the activity and/or expression of said polypeptide or polynucleotide.
A method for selecting a preclinical animal model which is predictive of affects of a test compound on P450 3A4 in humans comprising comparing in vitro activation of human PXR in the presence of the test compound with in vitro activation of PXRs from preclinical animal models in the presence of the test compound, wherein a PXR from a preclinical animal model exhibiting similar in vitro activation to the human PXR is indicative of the preclinical animal model being predictive of the affects of the test compound on P450 3A4 in humans.
Dependencies are inferred from the claim text.