Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Utility Patent
1999-11-29
2001-01-02
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Utility Patent
active
06169166
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in identifying compounds which may be antagonists, antagonists and/or inhibitors, and to production of such polypeptides and polynucleotides.
BACKGROUND OF THE INVENTION
The drug discovery process is currently undergoing a fundamental revolution as it embraces ‘functional genomics’, that is, high throughput genome- or gene-based biology. This approach is rapidly superceding earlier approaches based on ‘positional cloning’. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery.
Multi-specific drug transporters are present in cells having a barrier function such as intestinal epithelial and brain microvessel endothelial cells. Other tissues, for example, liver and kidney, also contain multi-specific transporters that can mediate the excretion of drugs and metabolites. Recently, it has been recognized that transporters encoded by genes such as mdr1 contribute to poor intestinal absorption and brain penetration of drugs. Information gained from using multi-specific transporters such as the mdr1 gene product in cell based, membrane based, binding or other assays could enhance drug formulation, selection of formulation excipients, and compound design.
SUMMARY OF THE INVENTION
The present invention relates to rat mdr1b2, in particular rat mdr1b2 polypeptides and rat mdr1b2 polynucleotides, recombinant materials and methods for their production. In another aspect, the invention relates to methods for identifying agonists and antagonists/inhibitors of the rat mdr1b2 gene, as well as compounds than neither agonize nor antagonize the rat mdr1b2 gene. This invention further relates to the generation of in vitro and in vivo comparison data to predict oral absorption and pharmacokinetics in man. Such a comparison of data will enable selection of drugs with optimal pharmacokinetics in man, i.e., good oral bioavailability, brain penetration, plasma half life, and minimum drug interaction.
The present invention further relates to methods for creating transgenic animals and knock-out animals. Furthermore, this invention relates to transgenic and knock-out animals obtained by using these methods. Such animal models are expected to provide valuable insight into the potential pharmacological and toxicological effects in humans of compounds that are discovered by the aforementioned screening methods. An understanding of how the rat mdr1b2 gene functions in these animal models is expected to provide an insight into treating and preventing human diseases including, but not limited to, cancer, inflammation, cardiovascular disease, central nervous system disorders, auto-immune and kidney disease.
REFERENCES:
Silverman et al., “Cloning and characterization a member of the rat multidrug resistance (mdr) gene Family, ” Gene 106:229-236, (1991).
Watson et al. Recombinant DNA, 2ndedition. Scientific American Books, WH Freman and Company pp. 453-470 (1992).
Brun Kimberly A.
Chenery Richard J
Ellens Harma
Feild John A
Yue Lin
Hecht Elizabeth J.
King William T.
Low Christopher S. F.
Ratner & Prestia
SmithKline Beecham Corporation
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