EP1322759A2 - Potassium channel interactors and uses therefor - Google Patents

Potassium channel interactors and uses therefor

Info

Publication number
EP1322759A2
EP1322759A2 EP01977260A EP01977260A EP1322759A2 EP 1322759 A2 EP1322759 A2 EP 1322759A2 EP 01977260 A EP01977260 A EP 01977260A EP 01977260 A EP01977260 A EP 01977260A EP 1322759 A2 EP1322759 A2 EP 1322759A2
Authority
EP
European Patent Office
Prior art keywords
seq
pcip
nucleic acid
polypeptide
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01977260A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kenneth Rhodes
Maria Betty
Huai-Ping Ling
Wenqian An
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Millennium Pharmaceuticals Inc
Original Assignee
Millennium Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/670,756 external-priority patent/US7078481B1/en
Application filed by Millennium Pharmaceuticals Inc filed Critical Millennium Pharmaceuticals Inc
Publication of EP1322759A2 publication Critical patent/EP1322759A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)

Definitions

  • Kv channel ⁇ -subunits fall into four sub-families named for their homology to channels first isolated from Drosophila: the Kvl, or S/z ⁇ /ter-related subfamily; the Kv2, or S/z ⁇ b-related subfamily; the Kv3, or S z ⁇ w-related subfamily; and the Kv4, or Shal- related subfamily.
  • Kv4.2 and Kv4.3 are examples of Kv channel ( ⁇ -subunits of the Shal-related subfamily.
  • a PCIP nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more identical to the amino acid sequence of SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO.10, SEQ ID NO:12, SEQ ID NO-14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:70, SEQ ID NO:40
  • an isolated nucleic acid molecule encodes the amino acid sequence of lv, 9q, ⁇ l9, W28559, KChIP4a, KChIP4b, 33b07, lp, and rat 7s protein.
  • nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98936, 98937, 98938, 98939, 98940,
  • the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 932-1527, 1548-1765, 1786-1871, 1908-2091, 2259-2265, or 2630-2654 of SEQ ID NO:35.
  • the nucleic acid molecules comprise nucleotides 932-1527, 1548-1765, 1786-1871, 1908-2091, 2259-2265, or 2630-2654 of SEQ ID NO.35.
  • the present invention provides a method for detecting the presence of PCIP activity in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of PCIP activity such that the presence of PCIP activity is detected in the biological sample.
  • Nucleic acid molecules corresponding to natural allelic variants and homologues of the PCIP cDNAs of the invention can be isolated based on their homology to the PCIP nucleic acids disclosed herein using the cDNAs disclosed herein, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.
  • amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
  • a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid
  • a chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term.
  • Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene.
  • Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, A.
  • a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae (O'Gorman et al (1991) Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio
  • determining the ability of the test compound to modulate PCIP activity can be accomplished by monitoring, for example, the I t0 current or the release of a neurotransmitter from a cell which expresses PCIP such as a cardiac cell.
  • Currents in cells e.g., the I t0 current
  • the cell can be of mammalian origin.
  • an assay of the present invention is a cell-free assay in which a PCIP protein or biologically active portion thereof is contacted with a test compound and the ability of the test compound to bind to the PCIP protein or biologically active portion thereof is determined.
  • Preferred biologically active portions of the PCIP proteins to be used in assays of the present invention include fragments which participate in interactions with non-PCIP molecules, e.g., potassium channels or fragments thereof, or fragments with high surface probability scores. Binding of the test compound to the PCIP protein can be determined either directly or indirectly as described above.
  • a membrane-bound form of an isolated protein e.g., a potassium channel
  • a solubilizing agent such that the membrane-bound form of the isolated protein is maintained in solution.
  • the PCIP sequences of the present invention can also be used to identify individuals from minute biological samples.
  • the United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel.
  • RFLP restriction fragment length polymorphism
  • an individual's genomic D ⁇ A is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification.
  • This method does not suffer from the current limitations of "Dog Tags" which can be lost, switched, or stolen, making positive identification difficult.
  • the sequences of the present invention are useful as additional D ⁇ A markers for RFLP (described in U.S. Patent 5,272,057).
  • the prognostic assays can be utilized to identify a subject having or at risk for developing a disorder associated with a misregulation in PCIP protein activity or nucleic acid expression, such as a potassium channel associated disorder.
  • the present invention provides a method for identifying a disease or disorder associated with aberrant PCIP expression or activity in which a test sample is obtained from a subject and PCIP protein or nucleic acid (e.g., mRNA or genomic DNA) is detected, wherein the presence of PCIP protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant PCIP expression or activity.
  • a test sample refers to a biological sample obtained from a subject of interest.
  • a test sample can be a biological fluid (e.g. , serum), cell sample, or tissue.
  • the human genomic 9q sequence (SEQ ID NOs:46 and 47) was isolated by screening a B AC genomic DNA library (Reasearch Genetics) using primers which were designed based on the sequence of the human 9qm cDNA. Two positive clones were identified (44802 and 721117) and sequenced.
  • EXAMPLE 5 EXPRESSION OF IV, 8T, AND 9Q mRNA IN RAT
  • 8t./9q mRNA appears to be concentrated in interneurons in addition to principal cells, and in all regions 8t/9q expression appears to be concentrated in neurons as apposed to glial cells.
  • Single- and double-label immunohistochemistry revealed that the PCIP and Kv4 polypeptides are precisely colocalized in many of the cell types and brain regions where PCIP and Kv4 mRNAs are coexpressed.
  • the human foil length pi 9 sequence was identified using RACE PCR.
  • the sequence of pl9 (also referred to as KChIP3) is shown in Figure 16.
  • the amino acid sequence of human pl9 is 92% identical to the mouse pl9 gene (SEQ ID NO:35).
  • TBLASTN searches using the protein sequence of human pi 9 revealed that human pi 9 is homologous to two sequences, Calsenilin (described in (1998) Nature Medicine 4: 1177- 1181) and DREAM, a Ca2+-dependent regulator of prodynorphin and c-fos transcription (described in Carrion et al. (1999) Nature 398: 80-84).
  • Human pl9 is 100%> identical at the nucleotide level to Calsenilin (but extends 3' to the published sequence) and 99% identical at the nucleotide level to DREAM.
  • TSP(Y)s Testes-specific proteins
  • NAPs Nucleosome Assembly Proteins

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Neurosurgery (AREA)
  • Biophysics (AREA)
  • Neurology (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Plant Pathology (AREA)
  • Toxicology (AREA)
  • Cardiology (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
EP01977260A 2000-09-27 2001-09-27 Potassium channel interactors and uses therefor Withdrawn EP1322759A2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US09/670,756 US7078481B1 (en) 1998-11-20 2000-09-27 Potassium channel interactors and uses therefor
US670756 2000-09-27
US703094 2000-10-31
US09/703,094 US7556938B1 (en) 1998-11-20 2000-10-31 Nucleic acids encoding potassium channel interactors
PCT/US2001/030463 WO2002026984A2 (en) 2000-09-27 2001-09-27 Potassium channel interactors and uses therefor

Publications (1)

Publication Number Publication Date
EP1322759A2 true EP1322759A2 (en) 2003-07-02

Family

ID=27100393

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01977260A Withdrawn EP1322759A2 (en) 2000-09-27 2001-09-27 Potassium channel interactors and uses therefor

Country Status (13)

Country Link
EP (1) EP1322759A2 (xx)
JP (1) JP2004525610A (xx)
KR (1) KR20030074604A (xx)
CN (1) CN1498271A (xx)
AU (1) AU2001296393A1 (xx)
BR (1) BR0114383A (xx)
CA (1) CA2420960A1 (xx)
CZ (1) CZ20031154A3 (xx)
EA (1) EA200300420A1 (xx)
IL (1) IL154962A0 (xx)
MX (1) MXPA03002557A (xx)
NO (1) NO20031369L (xx)
WO (1) WO2002026984A2 (xx)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067312B1 (en) 2001-09-19 2006-06-27 Myriad Genetics, Inc. PN7718 nucleic acids and use thereof
WO2004041193A2 (en) * 2002-11-01 2004-05-21 Decode Genetics Ehf. HUMAN TYPE II DIABETES GENE-Kv CHANNEL-INTERACTING PROTEIN (KChIP1) LOCATED ON CHROMOSOME 5
EP2353014A2 (en) * 2008-11-06 2011-08-10 Basf Se A screening assay for insecticides
CN105483276B (zh) * 2016-02-01 2019-06-11 成都望路医药技术有限公司 Kcnip4基因及其表达产物在直肠腺癌诊疗中的应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4758997A (en) * 1996-10-17 1998-05-11 Nps Pharmaceuticals, Inc. Potassium channel blocking compounds and their use
US6117989A (en) * 1998-03-26 2000-09-12 Incyte Pharmaceuticals, Inc. Human calcium-binding proteins
MXPA01004903A (es) * 1998-11-20 2003-03-10 Millennium Pharm Inc Agentes que interactuan con canales del potasio y usos de los mismos.
AU5151100A (en) * 1999-05-19 2000-12-05 Incyte Genomics, Inc. Extracellular signaling molecules
WO2001053312A1 (en) * 1999-12-23 2001-07-26 Hyseq, Inc. Novel nucleic acids and polypeptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0226984A2 *

Also Published As

Publication number Publication date
IL154962A0 (en) 2003-10-31
BR0114383A (pt) 2005-04-12
CA2420960A1 (en) 2002-04-04
JP2004525610A (ja) 2004-08-26
NO20031369D0 (no) 2003-03-26
MXPA03002557A (es) 2004-09-10
NO20031369L (no) 2003-05-22
KR20030074604A (ko) 2003-09-19
WO2002026984A3 (en) 2003-03-13
CZ20031154A3 (cs) 2003-09-17
EA200300420A1 (ru) 2004-04-29
CN1498271A (zh) 2004-05-19
AU2001296393A1 (en) 2002-04-08
WO2002026984A2 (en) 2002-04-04

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