WO2007136159A1 - Utilisation d'antagoniste de sphingosylphosphorylcholine pour restaurer l'expression de peptides antimicrobiens - Google Patents

Utilisation d'antagoniste de sphingosylphosphorylcholine pour restaurer l'expression de peptides antimicrobiens Download PDF

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Publication number
WO2007136159A1
WO2007136159A1 PCT/KR2006/005313 KR2006005313W WO2007136159A1 WO 2007136159 A1 WO2007136159 A1 WO 2007136159A1 KR 2006005313 W KR2006005313 W KR 2006005313W WO 2007136159 A1 WO2007136159 A1 WO 2007136159A1
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WIPO (PCT)
Prior art keywords
sphingosylphosphorylcholine
expression
antimicrobial peptides
hbd
antagonist
Prior art date
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PCT/KR2006/005313
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English (en)
Inventor
Hyoung June Kim
Hyuk Kim
Ki Sa Sung
Dae-Kwon Kim
Dae-Seok Sung
Jong Hee Park
Sun A Cho
Kwang Mi Kim
Chang-Hoon Lee
Jung Ju Kim
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Amorepacific Corporation
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Publication date
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Priority to KR1020087030865A priority Critical patent/KR101349198B1/ko
Publication of WO2007136159A1 publication Critical patent/WO2007136159A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2405/00—Assays, e.g. immunoassays or enzyme assays, involving lipids
    • G01N2405/08—Sphingolipids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders
    • G01N2800/202—Dermatitis

Definitions

  • the present invention relates to a method for restoring the expression levels of antimicrobial peptides (AMPs), e.g., in the skin of an atopic dermatitis patient, using sph- ingosylphosphorylcholine (SPC) antagonists, a use of SPC antagonists for the manufacture of a medicament for restoring the AMPs expression, and a method for screening an SPC antagonist by analyzing the ability of candidate compounds for restoring the expression level of AMPs.
  • AMPs antimicrobial peptides
  • SPC sph- ingosylphosphorylcholine
  • Sphingosylphosphorylcholine is a member of the lysosphingolipid family and has the form of N-deacylated sphingomyeline of the following formula.
  • SPC is a mitogen generated from sphingomyelin (SM) by SM N-deacylase (Higuchi
  • AMPs Antimicrobial peptides
  • pathogens such as bacteria, viruses and fungi
  • AMPs have been demonstrated to induce angiogenesis, wound healing and chemotaxis (Izadpanah A et al., J. Am. Acad. Dermatol. (2005), 52, 381-390), and have a structural feature of being positively charged and possessing hydrophilic and hydrophobic residues.
  • Human defensins can be classified into alpha and beta defensins according to their structural features.
  • the alpha defensins are arginine-rich monomeric polypeptides each composed of about 30-35 amino acids, and 6 isoforms thereof (HNP-I to -4, HD-5, and HD-6) have been identified in human.
  • 6 isoforms thereof HNP-I to -4, HD-5, and HD-6
  • beta-defensins each composed of about 41-50 amino acids
  • 11 isoforms have been biochemically identified in human serum (Biochemistry and Molecular Biology News (2006), 1-7)
  • 28 human beta- defensin genes and 43 mouse beta-defensin genes have been identified to date by the human genome project (B.C. Schutte et al., Proceedings of the National Academy of Sciences USA (2002), 99, 2129-2133).
  • HBD-I human beta defensins
  • HBD-2 is expressed in the skin, lung, respiratory tract, gum and tympanum, but is totally absent in urinary organs such as kidney and bladder, and salivary glands (J. Harder et al., Nature (1997), 387, 861).
  • HBD-3 is expressed in skin
  • HBD-4 is expressed in male genital organs and stomach.
  • HBD-I and HBD-3 are constitutively expressed whereas the expression of most
  • HBDs including HBD-2 and HBD-4 are inducible only in response to specific condition such as infection (J.M. Schroder et al., Int. J. Biochem. Cell Biol. (1999), 31, 645-651).
  • HBD-2 has been suggested to be upregulated by NF- ⁇ B through MEK1/2-ERK1/2 signal pathway (Tsutsumi-Ishii Y et al., J. Leukoc. Biol. (2002), 71, 154-162), and enhanced by TNF- ⁇ , IL- l ⁇ , IL- l ⁇ or LPS (KW Cha et al., Proc. Natl. Acad. Sci.
  • HBD-2 gene promoter region includes NF- ⁇ B binding sites.
  • HBD-4 has been reported to be inducible by microbes such as S. pneumoniae via PMA-PKC signal pathway (J.R. Garcia et al., FASEB J. (2001), 15, 1819-1821), and the expression level of HBD-3 is elevated in response to TNF- ⁇ , IL- l ⁇ and IFN- ⁇ .
  • the present inventors have therefore endeavored to establish the pathological mechanism of atopic dermatitis, and have found that SPC dramatically reduces the expression of AMPs, especially HBD-I to -4 which belong to the human defensin beta families and the expression thereof has been reported to decrease in the skin of AD patients, cathelicidin (LL-37), and dermcidin.
  • AMPs antimicrobial peptides
  • SPC sphingosylphospho- rylcholine
  • a method for restoring the expression of AMPs in a mammal in need of the restoration of the AMPs expression comprising the step of administering SPC antagonists in a therapeutic dose to the mammal.
  • an SPC antagonist for the manufacture of a medicament for restoring the expression of AMPs to normal levels in a mammal in need of such restoration.
  • a method for screening an antagonist of SPC comprising the steps of: 1) treating a subject with SPC or a derivative thereof to downregulate the expression of AMPs; and 2) treating the subject with a SPC antagonist candidate and analyzing the restored levels of the AMPs expression in the subject
  • FlG. 1 RT-PCR analysis results showing that the mRNA expression levels of
  • HBD-2, HBD-3 and DCD in HaCaT cells which are constitutive or induced by PMA, are suppressed in an SPC dose-dependent manner;
  • HBD-2 and HBD-3 in HaCaT cells which are induced by TNF- ⁇ , and suppressed by SPC, are restored by treating 2-amino-2-octyloxymethyl-propane-l,3-diol or N- (2-(naphthalen-2-yloxy)ethyl)prop-2-en-l-amine; and
  • HBD-I and HBD-2 in ICR mice induced by PMA and suppressed by SPC, is restored to normal levels by treating 2-amino-2-octyloxymethyl-propane-l,3-diol or N- (2-(naphthalen-2-yloxy)ethyl)prop-2-en- 1 -amine.
  • AMPs to normal levels may be any one of the known SPC antagonists which can inhibit the activity of SPC or antagonize the mechanism that SPC downregulates the AMPs expression.
  • the representative examples of the SPC antagonists include a competitive inhibitor which binds to active sites of SPC, a noncompetitive inhibitor which binds to a site other than active sites of SPC to inactivate the active sites, an inhibitor for the intracellular localization of SPC, a material degrading SPC or inducing the SPC degradation, and a blocking agent for the SPC-induced pathway of downregulating the expression of AMPs.
  • the SPC antagonists may be systemically or locally administered to a subject in need of restoration of the AMPs expression, such as a mammal including human with a disorder related to reduction of the AMPs expression, e.g., atopic dermatitis (AD).
  • a suitable single dose of the SPC antagonists in the inventive method may be determined in light of various relevant factors including the condition to be treated, the route of administration, the age and weight of the patient, and the severity of the patient's symptoms.
  • the present invention provides a method for screening a viable antagonist of SPC comprising the steps of 1) treating a subject with SPC or a derivative thereof to downregulate the expression of AMPs; and 2) treating the subject with an SPC antagonist candidates and analyzing the restored level of the AMPs expression in the subject.
  • the subject may be a test cell or mammal.
  • the test cell may be any one of the known cells, preferably keratinocytes, expressing AMPs or capable of expressing AMPs responsively to inducing materials, and the mammal may be a rodent such as a mouse, rat or marmot, perferably a hairless mouse.
  • step 1 SPC or a derivative thereof may be administered to a subject in a concentration ranging from about 1 nM to about 40 mM (from about 0.002%(w/w) to about 2%(w/w)).
  • concentration ranging from about 1 nM to about 40 mM (from about 0.002%(w/w) to about 2%(w/w)).
  • the concentration is less than 1 nM, the desired suppression of the AMPs expression cannot be achieved, and when more than 40 mM, the test cell may undergo morphological change, or adverse effects may occur in the mammal.
  • step 1 may further comprise treating the subject with an inducing material for the AMPs expression before or concurrently with the SPC treatment.
  • the inducing material for the AMPs expression may be selected from the group consisting of Ca + , TNF- ⁇ , IL- l ⁇ , IFN- ⁇ and phorbol 12-myristate 13-acetate (PMA), preferably TNF- ⁇ and PMA.
  • step 2 the subject undergone downregulation of the AMPs expression in step 1 may be treated with an SPC antagonist candidate and the restored levels of the AMPs expression are analyzed.
  • the expression levels of AMPs may be analyzed using one of the known methods employed for measuring gene or protein expression.
  • the gene expression of AMPs may be analyzed by RT-PCR, or blot analysis such as northern blot and using their genes or fragments thereof as probes, and the protein expression of AMPs, by way of conducting enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), sandwich assay, western blot, immunoblot or im- munohistochemical staining, using antibodies against AMPs.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • sandwich assay western blot
  • immunoblot immunoblot
  • im- munohistochemical staining using antibodies against AMPs.
  • SPC antagonists are useful for preventing and treating disorders related to the decreased expression of AMPs, such as atopic dermatitis, and a viable SPC antagonist can be efficiently screened by analyzing the restory levels of the AMPs gene or protein expression.
  • Example 1 Analysis for the reduction of the AMPs expression by SPC [49] [50] (1) Analysis in test cells [51] [52] Human keratinocyte cell line, HaCaT (Dr. N.E. Fusenig, Duetsches Krebs- abastechnik, Heidelberg, Germany) was seeded in a 6 well-plate at an amount of IxIO 5 cells/well, and cultured in Dulbecco's modified Eagle's medium (DMEM, Gibco BRL) supplemented with 10% fetal bovine serum (FBS) and 1% antibiotics (penicillin-streptomycin, Gibco ,USA) for 24 hours under the conditions of 37°C and 5% CO 2.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • antibiotics penicillin-streptomycin
  • mice were subjected to a treatment to their skin of the ear, back and abdomen regions by 20 ⁇ l of PMA in acetone (2.5 ⁇ g/ ⁇ l) for inducing the expression of AMPs, and concurrently, some of these mice were applied with 20 ⁇ l of 0.1% or 1% SPC, respectively, followed by the same SPC treatment after 6 hours therefrom. Some mice not treated with PMA were applied with only acetone (control group).
  • tissue samples were collected from the applied skins by 6 mm punching, and each sample was embedded in an OCT (optimal cutting temperature) compound, and frozen at -20°C. Each frozen tissue sample was sliced to a thickness of 4 ⁇ m, fixed on a slide glass, and incubated with anti-HBD-1 or anti-HBD-2 antibody (Santa cruse, USA) at room temperature for more than 1 hour. The obtained samples were each subjected to an immunohistochemical analysis using Envision kit (DAKO, USA). The results are shown in HG. 4 ((a) to (d)).
  • HBD-2 in the skin of ICR mice were significantly reduced in an SPC dose-dependent manner.
  • Example 2 Screening for SPC antagonists by analyzing restory level of the
  • HaCaT cells were seeded in a 6 well plate at a concentration of 1x10 5 cells/well, and cultured in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin (Gibco) for 24 hours under the conditions of 37°C and 5% CO .
  • HBD-2 together with 10 ⁇ M SPC for suppressing the AMPs expression. Then, they were each treated with 0, 0.1, 1 or 10 ppm of 2-amino-2-octyloxymethyl-propane-l,3-diol or N-
  • tissue samples were collected from the applied skins by 6 mm punching, embedded in an OCT (optimal cutting temperature) compound, and frozen at -20°C. Each frozen tissue sample was sectioned to a thickness of 4 ⁇ m, fixed on a slide glass, and incubated with anti-HBD-1 or anti-HBD-2 antibody (Santa cruse, USA) at room temperature for more than 1 hour. Each sample was subjected to an im- munohistochemical analysis using Envision kit (DAKO, USA) and the results are shown in HG. 4((d) to (f)). [75] As the results in FlG. 4 ((d) to (f)) show, the suppressed levels of the expression of
  • HBD-I and HBD-2 by SPC were restored to normal levels in the test groups treated with 2-amino-2-octyloxymethyl-propane-l,3-diol or N- (2-(naphthalen-2-yloxy)ethyl)prop-2-en- 1 -amine.
  • gagaccacag gtgccaattt 20 [141]

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Abstract

Selon la présente invention, SPC supprime l'expression de bêta-défensines humaines (HBD-1, HBD-2, HBD-3 et HBD-4), de cathélicidine (LL-37) et de dermcidine chez des patients atteints de dermite atopique et des antagonistes de SPC sont par conséquent utilisés pour prévenir et traiter des troubles associés à l'expression décroissante de peptides antimicrobiens (AMP).
PCT/KR2006/005313 2006-05-18 2006-12-08 Utilisation d'antagoniste de sphingosylphosphorylcholine pour restaurer l'expression de peptides antimicrobiens WO2007136159A1 (fr)

Priority Applications (1)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008069518A1 (fr) * 2006-12-08 2008-06-12 Amorepacific Corporation Composition pharmaceutique pour réguler la fonction de la sphingosylphosphorylcholine
WO2009069966A2 (fr) * 2007-11-30 2009-06-04 Amorepacific Corporation Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine
FR2965358A1 (fr) * 2010-09-24 2012-03-30 Oreal Utilisation cosmetique de la dermcidine, analogues ou fragments de celle-ci

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101349188B1 (ko) * 2006-10-17 2014-01-08 (주)아모레퍼시픽 Ｃｃｌ27/ｃｔａｃｋ의 발현을 억제시키는 방법
CN107918010A (zh) * 2017-11-27 2018-04-17 陕西科技大学 一种高灵敏液晶型非标记免疫传感器检测人类β防御素‑2的方法

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US6881546B2 (en) * 2000-12-22 2005-04-19 Medlyte, Inc., Sdsu Heart Institute Compositions and methods for the treatment and prevention of cardiovascular diseases and disorders, and for identifying agents therapeutic therefor

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US6881546B2 (en) * 2000-12-22 2005-04-19 Medlyte, Inc., Sdsu Heart Institute Compositions and methods for the treatment and prevention of cardiovascular diseases and disorders, and for identifying agents therapeutic therefor

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008069518A1 (fr) * 2006-12-08 2008-06-12 Amorepacific Corporation Composition pharmaceutique pour réguler la fonction de la sphingosylphosphorylcholine
WO2009069966A2 (fr) * 2007-11-30 2009-06-04 Amorepacific Corporation Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine
WO2009069966A3 (fr) * 2007-11-30 2009-08-20 Amorepacific Corp Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine
FR2965358A1 (fr) * 2010-09-24 2012-03-30 Oreal Utilisation cosmetique de la dermcidine, analogues ou fragments de celle-ci

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KR20090016595A (ko) 2009-02-16
KR101349198B1 (ko) 2014-01-09

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