Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-07-17
2002-05-21
Marschel, Ardin H. (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S569000, C514S617000
Reexamination Certificate
active
06391847
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to intracellular receptors, and ligands therefor. In a particular aspect, the present invention relates to methods for the modulation of processes mediated by invention receptors, as well as methods for the identification of compounds which effect such modulation.
BACKGROUND OF THE INVENTION
Nuclear receptors constitute a large superfamily of ligand-activated transcription factors. Members of this family influence transcription either directly, through specific binding to the promoters of target genes (see Evans, in
Science
240:889-895 (1988), or indirectly, via protein-protein interactions with other transcription factors (see, for example, Jonat et al., in
Cell
62:1189-1204 (1990), Schuele et al., in
Cell
62:1217-1226 (1990), and Yang-Yen et al., in
Cell
62:1205-1215 (1990)). The steroid/thyroid receptor superfamily includes receptors for a variety of hydrophobic ligands including cortisol, aldosterone, estrogen, progesterone, testosterone, vitamin D
3
, thyroid hormone and retinoic acid, as well as a number of receptor-like molecules, termed “orphan receptors” for which the ligands remain unknown (see Evans, 1988, supra). These receptors all share a common structure indicative of divergence from an ancestral archetype.
Identification of ligands for orphan receptors presents a significant challenge for the future since the number of orphan receptors which have been identified far exceeds the number of receptors with known ligands. Indeed, at least 40 genes, both vertebrate and invertebrate, have been identified which are structurally related to the steroid/thyroid receptor superfamily, but whose ligands are unidentified. Among these are Drosophila genes of known developmental significance including: the gap gene, knirps (Nauber et al., in
Nature
336:489-492 (1988), the terminal gene tailless, involved in patterning the head and tail regions (Pignoni et al., in
Cell
62:151-163 (1990), seven-up, which influences photoreceptor cell-fate (Mlodzik et al., in
Cell
60: 211-224 (1990), and ultraspiracle, a gene required both maternally and zygotically for pattern formation (Oro et al., in
Nature
347: 298-301 (1990)).
The identification of important Drosophila developmental genes as members of the steroid/thyroid hormone receptor superfamily suggests that vertebrate orphan receptors will have important developmental functions. Furthermore, the identification of ligands for orphan receptors could lead to the discovery of novel morphogens, teratogens and physiologically important hormones.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have identified new members of the steroid receptor superfamily of receptors, a representative member of which has been designated XOR-6. Invention receptors are responsive to hydroxy, mercapto or amino benzoates, and are expressed, for example, in
Xenopus laevis
embryos. XOR-6 is most closely, although distantly, related to the vitamin D3 receptor (VDR). The proteins are about 73% identical in amino acid sequence in the DNA-binding domains and about 42% identical in the ligand binding domain. Like VDR, XOR-6 has an extended D region between the DNA and ligand binding domains. Notably, the region amino-terminal to the XOR-6 DNA-binding domain is extremely acidic. This may influence its ability to activate target genes. XOR-6 is not restricted to Xenopus because southern blots show the presence of XOR-6-related sequences in a variety of other vertebrates. Indeed, a human genomic clone for an XOR-6 related gene has recently been isolated.
In accordance with a particular aspect of the present invention, there are also provided nucleic acid sequences encoding the above-identified receptors, as well as constructs and cells containing same, and probes derived therefrom. Furthermore, we have also discovered that hydroxy, mercapto or amino benzoates modulate the transcription activating effects of invention receptors.
REFERENCES:
patent: 4981784 (1991-01-01), Evans et al.
patent: 5312732 (1994-05-01), Evans et al.
patent: 5668175 (1997-09-01), Evans et al.
Evans, R. M., “The steroid and Thyroid Hormone Super Family”Science240: 889-895 (1988).
Hardwood et al. “Identificationof the pcaRKF Gene Cluster fromPseudomonas putida: Involvement in Chemotaxis, Biodegradation, and Transport of 4-Hydroxybenzoate”J. Bacterio.176: 6479-6488 (1994).
Mangelsdorf and Evans, “The RXR Heterodimers and Orphan Receptors”Cell83: 841-850 (1995).
Marder et al., “Blockade of Human Neutrophil Activation by 2-[2-propyl-3-[3-[2-ethyl-4-4(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid (L293111), A Novel Leukotriene B4Receptor Antagonist”Biochem. Pharm.49:1683-1690 (1995).
McDonnell et al., “Functional Domains of the Human Vitamin D3Receptor Regulate Osteocalcin Gene Expression”Molecular Endocrinology3: 635-644 (1989).
Smith et al., “A novel nuclear receptor superfamily member in Xenopus that associates with RXR, and shares extensive sequence similarity to the mammalian vitamin D3 receptor”Nucleic Acids Research22: 66-71 (1994).
Charpentier et al., J. Med. Chem., vol. 38, pp. 4993-5006, 1995.*
Laudet et al., The EMBO Journal, vol. 11, No. 3, pp. 1003-1013, 1992.
Blumberg Bruce
Evans Ronald M.
Umesono Kazuhiko
Marschel Ardin H.
Reiter Stephan E.
Spehar Teresa
The Salk Institute for Biological Studies
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