WO2000078933A2 - Nouvelles calpaines et leur utilisation - Google Patents

Nouvelles calpaines et leur utilisation Download PDF

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Publication number
WO2000078933A2
WO2000078933A2 PCT/EP2000/005261 EP0005261W WO0078933A2 WO 2000078933 A2 WO2000078933 A2 WO 2000078933A2 EP 0005261 W EP0005261 W EP 0005261W WO 0078933 A2 WO0078933 A2 WO 0078933A2
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WO
WIPO (PCT)
Prior art keywords
calpain
capnii
calpains
human
enzymatic activity
Prior art date
Application number
PCT/EP2000/005261
Other languages
German (de)
English (en)
Other versions
WO2000078933A3 (fr
Inventor
Neil T. Dear
Thomas Böhm
Achim Möller
Original Assignee
Basf Aktiengesellschaft
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 to SK1826-2001A priority Critical patent/SK18262001A3/sk
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to EP00945716A priority patent/EP1185673A2/fr
Priority to KR1020017016244A priority patent/KR20020011140A/ko
Priority to BR0011721-8A priority patent/BR0011721A/pt
Priority to CA002375477A priority patent/CA2375477A1/fr
Priority to IL14694000A priority patent/IL146940A0/xx
Priority to JP2001505676A priority patent/JP2003503023A/ja
Priority to MXPA01012937A priority patent/MXPA01012937A/es
Priority to AU59706/00A priority patent/AU5970600A/en
Publication of WO2000078933A2 publication Critical patent/WO2000078933A2/fr
Publication of WO2000078933A3 publication Critical patent/WO2000078933A3/fr
Priority to NO20015922A priority patent/NO20015922L/no
Priority to BG106186A priority patent/BG106186A/bg

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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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6472—Cysteine endopeptidases (3.4.22)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

Definitions

  • the invention relates to a new mammalian calpain CAPN11, its synthesis and its use.
  • Calpains are a superfamily of related proteins, some of which have been shown to act as calcim dependent cysteine proteases. Eight different calpains have been identified in mammals.
  • An increasing number of mammalian cal-pain homologs have been identified and the individual members can be divided into four classes based on the physical structure and the predicted properties.
  • Class A the "classic Calpaine” CAPNl, CAPN2, CAPN3 (p94); CAPN8 (nCL-2) and CAPN9 (nCL-4) are probably all protease-active and Ca 2+ dependent. They consist of a variable large (80 kDa) and an invariant small subunit (30 kDa).
  • Class B and D calpains CAPN5 (6.15) and CAPN7 (8) are protease-active, but most likely Ca 2+ -independent, the class C calpain, CAPN6, is unlikely to have any protease activity.
  • the calpains can also be divided into categories based on their expression pattern, with CAPN3, CAPN6, CAPN8 and CAPN9 having some tissue specificity.
  • the function of calpains is not known, although they have been associated with a large number of physiological processes and pathological conditions (overview in reference 17). To elucidate their function and evolutionary history, the identification of the entire spectrum of the Calpain family members is necessary.
  • the invention relates to the new polypeptide CAPN11 with the SEQ. - ID. -No. 2 disclosed amino acid sequence.
  • the new calpain protein CAPN11 has the characteristics typical of calpains, including potential protease and calcium binding domains. It has a very restricted tissue distribution and is mainly expressed in the testis. Radiation hybrid mapping was used to locate the gene on chromosome 6 in a region that is assigned to pl2. Phylogenetic analysis shows that CAPN11 is most closely related to CAPN1 and CAPN2 in mammals.
  • CAPN11 can be the human orthologon of the ⁇ / m calpain his.
  • the discovery of this new calpain emphasizes the complexity of the calpain family, whose members can be distinguished on the basis of protease activity, calcium dependency and tissue expression.
  • the cDNA nucleotide sequence of the CAPNII gene contains 2338 nucleotides (SEQ. ID. No. 1).
  • the cDNA sequence comes from a single mRNA by successfully amplifying the entire putative coding region from human testicular cDNA using flanking primers. Several cDNA clones were fully sequenced to rule out any PCR artifacts.
  • Calpaine gave the largest sequence homology (57.5%) for the chick cal pain ⁇ / m.
  • the mammalian calpaines were most similar to the human CAPNl (54.3% homology).
  • the least similar human calpain with only 18.7% homology was CAPN6.
  • the gene corresponding to this cDNA was designated CAPN11 by the Human Gene Nomenclature Committee.
  • the complete amino acid sequence of all identified human calpains was analyzed phylogenetically.
  • the results enable the human calpains to be classified into four main evolution groups (FIG. 2).
  • the first group is represented by CAPN5, CAPN6, CAPN7 and CAPN8, the second by CAPN1 and CAPN2, the third group by CAPN3 and CAPN9, and the fourth group comprises CAPN11.
  • the phylogenetic analysis thus suggests that CAPNII is a separate calpain subfamily.
  • CAPN11 in human tissues was examined by Northern and RNA dot blot analysis. Of the 50 tissue RAs examined, the CAPNII mRNA was most strongly expressed in the testis (FIG. 3A). The specificity of this signal was confirmed by Northern blot analysis and corresponded to an approximately 3 kb mRNA (FIG. 3D). In the thymus and in the mammary gland much weaker signals detected. However, the significance of this finding is unclear, since a further examination of Thymus RNA with Northern blot analysis did not produce any signal despite long exposure times (FIG. 3D and data not shown). A possible explanation would be that this weak signal is due to cross hybridization with related mRNAs. Thus, the testis is the major expression site of CAPNII, although we cannot rule out the possibility that the gene may be expressed in other, unexamined tissues.
  • This marker is located in the space between the microsatellite markers D6S1616 (59.6 cM) and D6S427 (73.9 cM) (7), and a marker in this space, D6S269, has been cytogenetically assigned to 6pl2 (5).
  • D6S1616 59.6 cM
  • D6S427 73.9 cM
  • D6S269 a marker in this space
  • the chick ⁇ / m calpain was the first member of the calpain family to be cloned (16). It was originally called m-calpain, but was reclassified after identifying other chick calpains that are most likely orthologous to the ⁇ - and m-calpaines from mammals (18). A mammalian ⁇ / m calpain has yet to be determined. However, since CAPN11 has a greater homology to the chick ⁇ / m calpain than to other mammalian calpains, this may be its orthologue.
  • CAPN3 skeletal muscle
  • CAPN6 placenta
  • CAPN8 possibly smooth muscles
  • CAPN9 stomach and small intestine
  • CAPN11 testes
  • Numerous proteases in the testis have been identified and are believed to be involved in processes such as tissue reorganization (20), regulation of spermatogenesis (14), sperm penetration of the zona pellucida (10) and fertility (13).
  • tissue reorganization (20), regulation of spermatogenesis (14), sperm penetration of the zona pellucida (10) and fertility (13).
  • CAPN11 is likely to be located intracellularly.
  • Another aspect of this invention relates to the use of the polypeptide CAPNII for the identification of substances which can inhibit the enzymatic activity of this polypeptide, so-called calpain inhibitors, in particular those calpain inhibitors which are selective for CAPNII.
  • Selectivity means that such calpain inhibitors inhibit the activity of CAPNII more than the activity of the other calpains mentioned above, preferably at least 10 times, more preferably 25 times more.
  • the enzyme activity of CAPNII is a Ca-dependent protease activity.
  • Another aspect of the invention relates to a method for identifying compounds which inhibit the enzyme activity of a polypeptide according to claim 1, comprising:
  • inhibitory compounds identified by the above-mentioned method are suitable for the treatment of diseases which are associated with or associated with an unphysiologically increased CAPNII activity, such as infertility in men.
  • Capn7 A highly divergent vertebrate calpain with a novel
  • TESPl Two novel testicular serine proteases, TESPl and TESP2, are present in the mouse sperm. acro- some. Biochem. Biophys. Res. Commun. 245: 658-665.
  • FIG. 1 Grouping the predicted amino acid sequence of CAPNII with other human calpains. The multiple grouping of the amino acid sequences was carried out using CLUSTAL W (19).
  • the putative start methionine for CAPNII (GGAatgG) corresponds to the minimal consensus sequence for the translation start site (RNNatgG, where R is a purine, ref. 11).
  • Amino acids that are identical to those of CAPNII 5 in the other proteins are shaded. Dashes indicate gaps that have been added to maximize alignment. Arrowheads indicate the three conserved amino acids that are part of the active center of the Calpaine.
  • the potential EF hand calcium binding domains of CAPN8 are underlined and numbered consecutively. The arbitrary domains of Calpain are specified.
  • FIG. 2 Rootless phylogenetic family tree of the family of the large subunit of human calpaine. The analysis was carried out with the PAUP program and the family tree with CLUSTREE from the HUSAR server of the German Cancer Research Center, Heidelberg (www.dkfz-heidelberg.de) was arranged. The lengths of the horizontal lines are proportional to the derived phylogenetic distances; the vertical lines have no meaning.
  • the CAPN7 sequence is from the mouse because there is little human nucleotide and protein sequence available. However, the human orthologue exists (see ref. 8), so the use of the mouse sequence for this comparison is justified.
  • the partial human CAPN8 sequence is the predicted translation of the EST clone AA026030 (Hillier et al., 1995, The WashU-Merck EST project, unpublished results). An amino acid translation of this clone shows high similarity to the rat CAPN8 sequence. No bootstrapping was done with this sequence because it is much shorter than the others. The bootstrapping value can therefore not be meaningfully compared with the values from comparisons of full-length sequences.
  • CAPNl The nomenclature specified by the Human Gene Nomenclature Committee is used. Previous names for the different calpains are: CAPNl - m-Calpain, CAPN2 - m-Calpain, CAPN3 - p94, nCl-1, CAPN8, nCL-2, CAPN9, nCL-4.
  • the EMBL accession numbers for the calpain sequences used are: CAPNl (P17655), CAPN2 (P07384), CAPN3 (P20807), CAPN5 (Y10656), CAPN6 (Y12582), CAPN7 (AJ012475) and CAPN9 (AF022799).
  • FIG. 3 Expression of CAPNII.
  • a 32 P-labeled DNA probe with an 800 base pair segment of the coding sequence of the human CAPNII cDNA was attached to a master blot (A), a nylon filter with dot blots of RNAs from 50 different human tissues or a Clontech Multi-tissue Northern blot (D) hybridizes.
  • the filters were washed with high stringency (6x SSC, 65 ° C). The exact location of the different RNAs on the dot blot filter is shown schematically (C). The RNAs on the Northern blot are indicated above the corresponding lanes.
  • Dot blot and Northern blot were re-hybridized with human ubiquitin (B) and b-actin DNA probes to determine the amounts of poly (A +) RNA applied.
  • the positions of the size markers (in kilobases) are given for the Northern blot.
  • the exposure times were: A, 72 hours; B, 24 hours; D, 48 hrs.
  • PBL peripheral blood leukocytes.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Reproductive Health (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gynecology & Obstetrics (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention concerne de nouvelles calpaïnes et leur utilisation.
PCT/EP2000/005261 1999-06-18 2000-06-07 Nouvelles calpaines et leur utilisation WO2000078933A2 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
IL14694000A IL146940A0 (en) 1999-06-18 2000-06-07 Novel calpains and their use
EP00945716A EP1185673A2 (fr) 1999-06-18 2000-06-07 Nouvelles calpaines et leur utilisation
KR1020017016244A KR20020011140A (ko) 1999-06-18 2000-06-07 신규 칼파인 및 그의 용도
BR0011721-8A BR0011721A (pt) 1999-06-18 2000-06-07 Polipeptìdeo, sequência de polinucleotìdeos, uso de um polipeptìdeo, processo para identificar compostos que inibem a atividade enzimática de um polipeptìdeo, e, uso de compostos
CA002375477A CA2375477A1 (fr) 1999-06-18 2000-06-07 Nouvelles calpaines et leur utilisation
SK1826-2001A SK18262001A3 (sk) 1999-06-18 2000-06-07 Kalpaíny a ich použitie
JP2001505676A JP2003503023A (ja) 1999-06-18 2000-06-07 新規カルパインおよびその使用
MXPA01012937A MXPA01012937A (es) 1999-06-18 2000-06-07 Calpainas novedosas y su uso.
AU59706/00A AU5970600A (en) 1999-06-18 2000-06-07 Novel calpains and their use
NO20015922A NO20015922L (no) 1999-06-18 2001-12-04 Nye calpainer og anvendelse derav
BG106186A BG106186A (bg) 1999-06-18 2001-12-06 Нови калпаини и използването им

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19928021.5 1999-06-18
DE19928021A DE19928021A1 (de) 1999-06-18 1999-06-18 Neue Calpaine und deren Verwendung

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WO2000078933A2 true WO2000078933A2 (fr) 2000-12-28
WO2000078933A3 WO2000078933A3 (fr) 2001-07-26

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PCT/EP2000/005261 WO2000078933A2 (fr) 1999-06-18 2000-06-07 Nouvelles calpaines et leur utilisation

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EP (1) EP1185673A2 (fr)
JP (1) JP2003503023A (fr)
KR (1) KR20020011140A (fr)
CN (1) CN1373808A (fr)
AR (1) AR024573A1 (fr)
AU (1) AU5970600A (fr)
BG (1) BG106186A (fr)
BR (1) BR0011721A (fr)
CA (1) CA2375477A1 (fr)
DE (1) DE19928021A1 (fr)
HU (1) HUP0201800A2 (fr)
IL (1) IL146940A0 (fr)
MX (1) MXPA01012937A (fr)
NO (1) NO20015922L (fr)
PL (1) PL353004A1 (fr)
SK (1) SK18262001A3 (fr)
TR (1) TR200103662T2 (fr)
WO (1) WO2000078933A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001016336A1 (fr) * 1999-09-02 2001-03-08 Lexicon Genetics Incorporated Proteases humaines dependantes du calcium et polynucleotides les codant
WO2011137372A1 (fr) 2010-04-30 2011-11-03 Abbott Cardiovascular Systems Inc. Cathéter à ballonnet amélioré se gonflant et se dégonflant rapidement

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19737105A1 (de) * 1997-08-26 1999-03-04 Basf Ag Neue gewebsspezifische Calpaine, ihre Herstellung und Verwendung
WO2000058473A2 (fr) * 1999-03-31 2000-10-05 Curagen Corporation Acides nucleiques comprenant des phases de lecture ouverte codant des polypeptides; «orfx»

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19737105A1 (de) * 1997-08-26 1999-03-04 Basf Ag Neue gewebsspezifische Calpaine, ihre Herstellung und Verwendung
WO2000058473A2 (fr) * 1999-03-31 2000-10-05 Curagen Corporation Acides nucleiques comprenant des phases de lecture ouverte codant des polypeptides; «orfx»

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DEAR T NEIL ET AL: "CAPN11: A calpain with high mRNA levels in testis and located on chromosome 6." GENOMICS, Bd. 59, Nr. 2, 15. Juli 1999 (1999-07-15), Seiten 243-247, XP002159274 ISSN: 0888-7543 *
ZHANG WENLI ET AL: "The major calpain isozymes are long-lived proteins. Design of an antisense strategy for calpain depletion in cultured cells." JOURNAL OF BIOLOGICAL CHEMISTRY, Bd. 271, Nr. 31, 1996, Seiten 18825-18830, XP002159273 ISSN: 0021-9258 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001016336A1 (fr) * 1999-09-02 2001-03-08 Lexicon Genetics Incorporated Proteases humaines dependantes du calcium et polynucleotides les codant
US6433153B1 (en) 1999-09-02 2002-08-13 Lexicon Genetics Incorporated Human calcium dependent proteases and polynucleotides encoding the same
WO2011137372A1 (fr) 2010-04-30 2011-11-03 Abbott Cardiovascular Systems Inc. Cathéter à ballonnet amélioré se gonflant et se dégonflant rapidement

Also Published As

Publication number Publication date
NO20015922D0 (no) 2001-12-04
HUP0201800A2 (en) 2002-09-28
IL146940A0 (en) 2002-08-14
SK18262001A3 (sk) 2002-09-10
AR024573A1 (es) 2002-10-16
BR0011721A (pt) 2002-03-05
CN1373808A (zh) 2002-10-09
NO20015922L (no) 2002-02-12
AU5970600A (en) 2001-01-09
EP1185673A2 (fr) 2002-03-13
PL353004A1 (en) 2003-09-22
CA2375477A1 (fr) 2000-12-28
MXPA01012937A (es) 2002-07-30
DE19928021A1 (de) 2000-12-21
JP2003503023A (ja) 2003-01-28
KR20020011140A (ko) 2002-02-07
BG106186A (bg) 2002-12-29
TR200103662T2 (tr) 2002-05-21
WO2000078933A3 (fr) 2001-07-26

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