WO2001019389A1 - Remedes pour l'arthrite rhumatoide et proteine fusionnee - Google Patents

Remedes pour l'arthrite rhumatoide et proteine fusionnee Download PDF

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Publication number
WO2001019389A1
WO2001019389A1 PCT/JP2000/006180 JP0006180W WO0119389A1 WO 2001019389 A1 WO2001019389 A1 WO 2001019389A1 JP 0006180 W JP0006180 W JP 0006180W WO 0119389 A1 WO0119389 A1 WO 0119389A1
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Prior art keywords
cbp
rheumatoid arthritis
creb
recognition region
partial peptide
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PCT/JP2000/006180
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English (en)
Japanese (ja)
Inventor
Toshihiro Nakajima
Kusuki Nishioka
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St. Marianna University School Of Medicine
Santen Pharmaceutical Co., Ltd.
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Application filed by St. Marianna University School Of Medicine, Santen Pharmaceutical Co., Ltd. filed Critical St. Marianna University School Of Medicine
Priority to AU68771/00A priority Critical patent/AU6877100A/en
Publication of WO2001019389A1 publication Critical patent/WO2001019389A1/fr

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    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention provides a synovial cell proliferation inhibitor capable of introducing a phosphorylated CREB recognition region partial peptide of CBP, which is a phosphorylated CREB coactivator, into the synovial cell nucleus of rheumatoid arthritis, and
  • the present invention relates to a therapeutic agent for rheumatoid arthritis, which comprises a phosphorylated CREB recognition region partial peptide of CBP, which is a phosphorylated CREB coactivator, as an active ingredient.
  • RNA-level responses to various stimuli such as hormones and growth factors, in particular, the activation or inactivation of transcription of DNA to RNA are important steps directly involved in cell growth and activation. Transcription is the root of life support. Thus, transcriptional regulation is directly involved in life support in this sense. Regulation of DNA transcription is mediated by a group of mainly proteinaceous factors called transcription factors. For example, in the hormone Zc AMP / protein kinase A (PKA) pathway, the binding of hormones to hormone receptors increases adenylate cyclase activity, and PKA is activated when intracellular c AMP levels increase.
  • PKA protein kinase A
  • CRE binding protein a transcription factor CREB
  • CBP CREB binding protein
  • KIX such as 1S CBP and P300.
  • the structure and amino acid sequence of the KIX domain are already known (eg, Cell, Vol. 91, pp. 741-752, December 12, 199 7).
  • Rheumatoid arthritis is a chronic inflammatory disease of which the cause is currently unidentified, with polyarthritis as the main symptom.
  • the disease progresses with inflammatory infiltration of the synovium, proliferation of synovial cells, stratification and angiogenesis.
  • the cause of synovial cell hyperfunction which plays an important role in the pathogenesis of rheumatoid arthritis, It has not been fully elucidated yet, and there are many unclear points regarding abnormalities in the function control mechanism of synovial cells themselves. Summary of the Invention
  • the present invention relates to a therapeutic agent for rheumatoid arthritis and an agent for inhibiting the growth of synovial synovial cells, and in particular, a transcription factor expression mechanism for the proliferation and differentiation of rheumatoid arthritis synovial cells exhibiting abnormal function control mechanisms. It is an object of the present invention to provide a therapeutic agent for rheumatoid arthritis and a synovial cell proliferation inhibitor which can be suppressed at a level.
  • the present invention provides a therapeutic agent for rheumatoid arthritis and an agent for inhibiting synovial cell proliferation of a joint, which comprises a phosphorylated CREB recognition region of CBP, which is a phosphorylated CREB coactivator, as an active ingredient.
  • the partial peptide of the phosphorylated CREB recognition region of CBP is all or part of the KIX domain of CBP, in particular, derived from human or mouse.
  • the phosphorylated CREB recognition region partial peptide of CBP can act as a dominant negative body in the synovial cell nucleus.
  • the present invention is also a therapeutic agent for treating rheumatoid arthritis, which comprises administering a partial peptide of a phosphorylated CREB recognition region of CBP bound to a partial peptide of the antennadia protein.
  • a nuclear localization signal is bound to the phosphorylated CREB recognition region partial peptide of CBP bound to the partial peptide of the antenna dia protein.
  • the present invention further relates to a sequence represented by SEQ ID NO: 2 in the sequence listing, a sequence represented by SEQ ID NO: 3 in the sequence listing, and residues 553 to 679 (KIX 10.4) of mouse CBP. It is also a fusion protein characterized by consisting of a sequence.
  • the present invention still further relates to a pharmaceutical composition containing the above-mentioned fusion protein as an active ingredient, particularly a therapeutic agent for rheumatoid arthritis.
  • the fusion protein has a daltathione-1 S-transferase domain cleavable with thrombin bound thereto.
  • the therapeutic agent for rheumatoid arthritis and the synovial cell proliferation inhibitor of the present invention comprise, as an active ingredient, a phosphorylated CREB recognition region partial peptide of CBP, which is a phosphorylated CREB coactivator.
  • This active ingredient can be introduced into the nucleus of synovial cells in rheumatoid arthritis to exert an effect of inhibiting the proliferation of articular synovial cells.
  • the partial peptide has an amino acid sequence of a phosphorylated CREB recognition region of CBP, which is a phosphorylated CREB coactivator. Phosphorylation of CBP
  • the CREB recognition region is called KIX.
  • the serine residue which is the 133rd amino acid residue (mouse) of CREB
  • the CREB containing this 133 serine residue Is known to bind to a region called the kinase-inducible domain (KID, amino acid residues 101-160 (mouse). SEQ ID NO: 4 in the sequence listing). Cell. Biol., Vol. 16, No. 2, 694—703 (1996)).
  • the KID domain has two parallel helix regions A and ct B.
  • the amino acid sequence of this region is extremely conserved irrespective of the origin, especially the serine residue located at the ⁇ -terminal side of the ⁇ B helix. Is common to all as far as it is known.
  • This serine residue is, for example, residue 133 in mouse and corresponds to residue 118 in human. Phosphorylation of this serine residue is essential for binding to KIX.
  • the number of this serine residue in the KID domain varies depending on the origin. For convenience, the KID of each origin is a serine residue corresponding to residue 133 in mouse or rat, unless otherwise specified. It is called No. serine residue.
  • the IX protein has three helical regions ⁇ 1, hi2 and ⁇ 3, and two short three. Includes helix regions G1 and G2. These regions include, for example, in the mouse KIX protein, an ⁇ 1 helix spanning glutamine 579-isoloisin 611, an arginine 623— ⁇ 2 helix spanning tyrosine 640, Ginine 646— ⁇ 3 helix over lysine 662, tryptophan 59 1—G1 over histidine 594 and G2 over proline 617—lysine 621.
  • arginine residue in helix ⁇ 1 (arginine 600 in mouse KIX) is considered to be important for stabilizing the KIX protein.
  • IX This secondary structure of IX protein is commonly provided in various organisms, for example, human and mouse CBP, human and mouse P300, Drosophila CBP, R10E1 1. 1, K03H 1.10, etc. all have the above secondary structure (eg, Cell, Vol. 91, 741-752, 1997).
  • KIX proteins have amino acid sequences that differ depending on the species.However, hydrophobic residues important for interaction with KID are conserved, and all amino acids in the various KIX proteins exemplified above have the same amino acid sequence. However, they belong to the same family.
  • various KIX proteins having the above-mentioned characteristics, for example, human and mouse CBP KIX, human and mouse ⁇ 300 ⁇ IX, Drosophila CBP KIX, R10E11.1, K03H1.10.
  • the major part of the amino acid sequence of these KIX proteins has the above-mentioned structure common to CBP protein, R10E11.1, and ⁇ 03 ⁇ 1.10. Amino acid residue numbers of the ⁇ IX domain in proteins are generally different.
  • the major part of the amino acid sequence of these IX proteins is described, for example, in FIG. 1A of Cell, Vol. 91, 741-752 (1977).
  • the partial peptide may be human or mouse KIX (amino acid residues 456 to 680; mouse amino acid residues 45 55 to 679) shown in SEQ ID NO: 1 in the sequence listing. Les ,.
  • Examples of the partial peptide include a part of KIX of human / mouse CBP, for example, residues 554/553 to 679/680 (also referred to as “KIX SZB”), 5 54 553 residues to 6 79/680 residues (KIX 10. No. 4)), residues 577Z5 76 to 679/680 (also referred to as “KIX 5.4”), 577/5 residue 76 to 662/66 1 residue It may be a peptide having a base sequence (also referred to as “KIX 5.6”). Of these, XS / B, KIX 10.4, and X5.4 are preferred.
  • residues 456/455 to 598/597 residues also referred to as “KIX II”
  • residues 617 to 616 to residues 680/679 residues 680/679
  • residues 5775576 to 649-648 also referred to as “KIX 5.1.2”.
  • the above-mentioned examples are non-limiting listings of substances that can be used in the present invention.
  • the above-mentioned IX protein secondary structure and KID Amino acid substitutions that do not affect hydrophobic interaction are also applicable to the present invention.
  • the gene sequence of the KIX domain corresponding to residues 586 to 679 of mouse CBP is amplified by PCR, inserted into an appropriate expression vector, and introduced into E. coli. Then, the cultured cells are collected, and the supernatant obtained by ultrasonic treatment and centrifugation is applied to an FP LC column to obtain a protein fraction and purified.
  • Phosphorylation of the CB ⁇ CREB recognition domain partial peptide is introduced into the synovial nucleus of the rheumatoid arthritis joint, along with chemicals such as microinjection, electroporation, scrape bite-dating, and calcium phosphate.
  • chemicals such as microinjection, electroporation, scrape bite-dating, and calcium phosphate.
  • an internalization vector derived from a home domain which will be described below.
  • the Drosophila transcription factor antenna dia is a DNA-binding protein with a home domain, but the home domain (60 amino acid residues) of this antenna dia translocates through the cell membrane. It is known. In recent years, the minimum amino acid sequence required for this antenna media transfer has been determined. This region is a third helix consisting of 16 amino acid residues consisting of residues 43 to 58 of the homeodomain of the antenna media (SEQ ID NO: 2 in the sequence listing). This region (hereinafter also referred to as Ant_Mini) or the home domain of the antenna media containing this region is preferably bound to a physiologically active substance of 10 kDa or less, for example, a protein, a nucleic acid, or another compound. This allows efficient and stable introduction into cells.
  • the third helix structure itself is not always necessary for exerting the transfer function.For example, even if glutamine 50 is replaced with proline, or isofisine 45, glutamine 50, and lysine 55 are each substituted. Replacement with proline reduces translocation into the nucleus but allows translocation into cells.
  • the reverse sequence of the 16 amino acid residue sequence represented by SEQ ID NO: 2 in the above sequence listing (residue from arginine at residue 43 to lysine at residue 58), that is, the above amino acid sequence in reverse order from N-terminal to C-terminal
  • the synthetic peptide is arranged from the lysine at residue 58 to the arginine at residue 43, the ability to enter the nucleus is maintained.
  • a peptide in which the above 16 amino acid residue sequence is composed of D amino acids may be used.
  • the transfer function is not necessarily inhibited (for example, Curr ent Op In io i n i n N e u r
  • a partial peptide of antennadia is introduced by binding to Mini or a home domain containing the same.
  • nuclear localization signal for introduction into the nucleus of the synovial cells.
  • Nuclear localizationlessness sign nanore nanore (nucl ear loc aliiz ations
  • the fusion protein preferably comprises Ant-Mini or a homeodomain containing the same, a nuclear localization signal, and a partial peptide of the phosphorylated CREB recognition region of CBP.
  • the nuclear localization signal may be, for example, a basic amino acid cluster (SEQ ID NO: 3 in the sequence listing) such as SV40 virus large T antigen, a bipolar signal such as nucleoplasmin, or the like.
  • the maximum number of peptides that can be transferred and introduced by using partial peptides of antenna media is about 100 amino acid residues (Curent Opinionin Neurobiology, 1996, 6: 629). — 6 3 4)
  • the present invention by including a nuclear localization signal, even a longer peptide can be introduced into the nucleus.
  • Examples of the method for preparing the fusion protein include: a) phosphorylation of ⁇ 8? £ B recognition region partial peptide, or, if applicable, phosphorylation of CBP to which a nuclear localization signal is added CREB recognition region A peptide in which a thiol-protected cysteine is linked to a peptide, an internalization vector Ant-Mini or a thiol-protected cysteine at the end of a homeodomain containing the same. To form an S--S bond between the two through deprotection of the thiol.b) Continuously connect the internalization vector with the phosphorylated CR EB recognition region partial peptide of CBP. And synthesizing them into a series of fusion proteins.
  • the phosphorylated CREB recognition region partial peptide of CBP can bind to the N-terminus of Ant-Mini, but does not exclude binding to the C-terminus.
  • a daltathione-1 S-transferase (GST) domain which can be cleaved with thrombin, is bound to the fusion protein.
  • the daltathione-S-transferase domain is a protein with a molecular weight of 260,000 and cannot translocate into cells. Then, the fusion protein can be translocated into cells by cutting off the fusion protein with thrombin. Therefore, the fusion protein can be transferred into cells only in the presence of thrombin, and the introduction of the fusion protein into cells can be controlled.
  • the fusion protein for example, Ant-Mini or a homeodomain containing the same, a nuclear localization signal, and CBP Phosphorylated CREB recognition region Fusion proteins consisting of partial peptides serve this purpose.
  • the GST fusion protein can be prepared, for example, by incorporating the above fusion protein gene sequence into an expression vector capable of expressing a fusion protein of the target protein and the GST domain, and placing the gene fusion vector in an appropriate host. And a method of expressing the same.
  • expression vectors commercially available expression vectors can be used.
  • a phosphorylated CREB recognition region partial peptide of CB which is a phosphorylated CREB coactivator
  • CB which is a phosphorylated CREB coactivator
  • a dominant negative body that is, a peptide that binds to the KID region of phosphorylated CREB competitively with CBP.
  • Rheumatoid arthritis can be introduced into synovial cell nuclei. Since the above phosphorylated CREB recognition region partial peptide can bind to a region called ⁇ £ 8!: 1D, it blocks the binding of phosphorylated CREB coactivator, CBP, and transcribes it. It is considered to prevent the start.
  • the fusion protein of the present invention may be able to suppress the proliferation and activation of joint synovial cells in the lesions of patients with rheumatoid arthritis, and is expected to be useful as a therapeutic agent for rheumatoid arthritis. .
  • the method may include a means for transporting the active ingredient to a target tissue.
  • Example 1 Preparation of KIX fusion protein
  • a gene sequence encoding mouse IX was prepared by the method described in Chrivia et al., Nature 365, 855-8559 (1993). And amplified by the PCR method.
  • p GEX-2T manufactured by Amersham Pharmacia Biotech
  • the Ant-Mini gene-NLS gene-KIX gene was incorporated into the vector and expressed in E.co1i.
  • the resulting mixture was purified by a daltathione-Sepharose column to obtain a KIX fusion protein consisting of N-terminal, GST domain, Ant-Mini domain, NLS domain, KIX domain, and C-terminal.
  • Ant—Mini used the amino acid sequence of SEQ ID NO: 2 in the sequence listing
  • NLS used the amino acid sequence of SEQ ID NO: 3 in the sequence listing.
  • Synovial cells were obtained by removing blood cells from synovial tissue obtained with consent at the time of knee surgery in patients with rheumatoid arthritis and then counting the cells on a 96-well cultured plastic plate (100 microliters). at 1 X 1 0 4 Zw e 1 1 conditions were used after 3-5 passages cultured in 2% FCS-DMEM culture medium.
  • the GST / Ant—Mini / NL S / KIX fusion protein obtained in Example 1 was treated with thrombin to obtain Ant—Mini / NL SZK.
  • the IX fusion protein was added to a concentration of 5 / ig gml, 10 ⁇ g / m 125 ⁇ g / m I, 50 ⁇ g / m 1 and 100 g / m 1 .
  • FGF fibroblast growth factor
  • Table 1 The results are shown in Table 1. The numerical values are relative values when the control is 100. The case where no FGF was added was also shown. When FGF was not added, it was also confirmed that the addition of the fusion protein did not affect the proliferation up to at least 50 ⁇ g Zm1. table 1
  • the present invention can provide a novel introduction method capable of rapidly introducing an unprecedented dominant negative CBP-KIX into the synovial cell nucleus of a joint. Proliferation and differentiation of rheumatoid arthritis synovial cells can be suppressed at the level of transcription factor expression mechanism. Also, a therapeutic agent for rheumatoid arthritis and a synovial cell proliferation inhibitor for arthritis can be provided using the dominant negative body as an active ingredient.
  • the pharmaceutical composition containing the fusion peptide of the present invention as an active ingredient can be used as a synovial cell proliferation inhibitor and a therapeutic agent for rheumatoid arthritis.

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Abstract

La présente invention concerne des remèdes destinés à l'arthrite rhumatoïde et aux inhibiteurs de prolifération de cellules d'une synoviale articulaire, en particulier des remèdes destinés aux inhibiteurs de prolifération de cellules de synoviale articulaire et d'arthrite rhumatoïde capables d'inhiber la prolifération et la différenciation des cellules de synoviale articulaire et d'arthrite rhumatoïde dont le mécanisme de régulation des fonctions est anormal au niveau du mécanisme d'expression des facteurs de transcription. Ces remèdes destinés aux inhibiteurs de prolifération de cellules de synoviale articulaire et d'arthrite rhumatoïde contiennent, sous forme de composant actifs, la région de reconnaissance de CREB phosphorylé de CBP qui est un coactivateur de CREB phosphorylé, et une protéine fusionnée qui comprend la séquence représentée par SEQ ID NO:2 dans la liste des séquences, la séquence représentée par SEQ ID NO:3 dans la liste des séquences et la séquence constituée par les résidus 553 à 679 (KIX 10.4) de CBP de souris.
PCT/JP2000/006180 1999-09-10 2000-09-11 Remedes pour l'arthrite rhumatoide et proteine fusionnee WO2001019389A1 (fr)

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AU68771/00A AU6877100A (en) 1999-09-10 2000-09-11 Remedies for rheumatoid arthritis and fused protein

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JP11/256872 1999-09-10
JP25687299 1999-09-10

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
D. PARKER ET AL.: "Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism", MOLECULAR AND CELLULAR BIOLOGY, vol. 16, no. 2, February 1996 (1996-02-01), pages 694 - 703, XP002935859 *
NOBORU SUZUKI ET AL.: "Mansei kansetsu rheumatism kanja kansetsu katsumaku saibou ni okeru tensha inshi hatsugen", IGAKU NO AYUMI, vol. 182, no. 9, 1997, pages 586 - 589, XP002935858 *
PROCHIANTZ A.: "Getting hydrophilic compounds into cells: Lessons from homeopeptides", CURRENT OPINION IN NEUROBIOLOGY, vol. 6, no. 5, 1996, pages 629 - 634, XP002935860 *
TOSHIHIRO NAKAJIMA: "Tensha seigyo ni motozuita doumyaku kouka shou chiryouhou no kakuritsu", UEHARA KINEN SEIMEI KAGAKU ZAIDAN KENKYU HOUHOKUSHU, vol. 10, 1996, pages 294 - 295, XP002935862 *
YOSHIHIRO YONEDA ET AL.: "A long synthetic peptide containing a nuclear localization signal and its flanking sequences of SV40 T-antigen directs the transport of IgM into the nucleus efficiency", EXPERIMENTAL CELL RESEARCH, vol. 201, 1992, pages 313 - 320, XP002935861 *

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