JP6158712B2 - 新規合成ペプチド及びそれらの使用 - Google Patents
新規合成ペプチド及びそれらの使用 Download PDFInfo
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- JP6158712B2 JP6158712B2 JP2013550864A JP2013550864A JP6158712B2 JP 6158712 B2 JP6158712 B2 JP 6158712B2 JP 2013550864 A JP2013550864 A JP 2013550864A JP 2013550864 A JP2013550864 A JP 2013550864A JP 6158712 B2 JP6158712 B2 JP 6158712B2
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- peptides
- peptide
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- A61P17/06—Antipsoriatics
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
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Description
(配列中、
X1は、C、L、W、K、又はRであり、
X2は、C、F、K、W、又はRであり、
X3は、L、又はRであり、
X5は、L、K、又はRであり、
X7は、N、S、A、L、W、K、又はRであり、
X8は、M、W、又はSであり、
X9は、R、又はVであり、
X11は、V、A、H、L、又はRであり、及び
X12は、R、L、又はWである)
及びこれらのペプチドの機能的に同等の変異体(variant)、に関する。
X1は、W、K、又はRであり、
X2は、C、K、又はRであり、
X3は、L、又はRであり、
X5は、L、又はRであり、
X7は、W、又はKであり、
X8は、M、又はWであり、
X9は、R、又はVであり、
X11は、V、A、又はRであり、及び
X12は、R、又はLである)
及びこれらのペプチドの機能的に同等の変異体を含む。
(配列中、
X1は、Q、R、又はNであり、
X2は、S、R、又はKであり、
X3は、E、R、又はLであり、
X4は、A、R、又はFであり、
X5は、T、K、R、H、Q、又はEであり、
X6は、K、T又はSであり、
X7は、R、F、又はLであり、
X8は、F、K、又はAであり、
X11は、L、R、又はAであり、
X13は、N、又はQであり、及び
X18は、L、R、又はAである)
及びこれらのペプチドの機能的に同等の変異体に関する。
X1は、Q、R、又はNであり、
X3は、E、R、又はLであり、
X4は、A、R、又はFであり、
X5は、T、K、R、Q、又はEであり、
X6は、K、T、又はSであり、
X7は、R、F、又はLであり、
X8は、F、K、又はAであり、
X11は、L、R、又はAであり、及び
X18は、L、R、又はAである)
及びこれらのペプチドの機能的に同等の変異体を含む。
1)一般に、炎症及び/又は炎症から生じる病状の治療、及び具体的には、
2a)腸;クローン病(Morbus Crohn)、大腸炎、潰瘍性大腸炎、
2b)関節;関節リウマチ、関節炎、関節症、筋痙攣、筋断裂、筋障害、筋挫傷、筋捻挫を含む筋肉の局所性障害、
2c)皮膚;乾癬、湿疹(湿疹(excema))皮膚炎、ざ瘡、
2d)心臓;心膜炎、心内膜炎、心不全、
2e)疼痛;(さらに以下の2fで特定)、
2f)神経系;アルツハイマー、多発性硬化症、手根管症候群、椎間板ヘルニア、頸部リゾパシー(Cervical rhizopathy)、ベル麻痺(Bells palsy)、急性脊髄損傷、脊髄圧迫、脊柱管狭窄、帯状疱疹後神経痛、ウィルス性脳炎、ウィルス性髄膜炎、メニエール病、ポリオ及びポリオ後合併症(postpolio complication)、慢性炎症性脱髄性多発性ニューロパチー、多発性ニューロパチー、三叉神経痛(Trigminal neuralgia)、慢性てんかん性疾患、
2g)感覚器官;緑内障、
2h)粘膜表面;(化学/放射線療法の結果生じる炎症)、
2i)アレルギー;
2j)自己免疫疾患
が例示される。
3a)様々な組織、例えば、皮膚、筋肉、腱、神経組織、血管、及び体の様々な部位、例えば、眼、耳、声帯、手、脊髄、腹腔内、胸腔内、頭蓋腔内、口腔、婦人科医学に関する処置、子宮内膜症、包茎における外科的処置、
3b)ざ瘡、
3c)肥厚性瘢痕及びケロイド、
3d)胸膜炎、
3e)腹膜透析、
3f)急性及び慢性創傷
が例示される。
4a)がん、
4b)関節リウマチ
の治療のために好適である。
5a)抗菌効果;
上及び下気道(扁桃炎、副鼻腔炎、肺炎、慢性閉塞性肺疾患、嚢胞性線維症など)、
眼の感染(例えば、結膜炎)、
尿路感染、
性感染疾患(コンドームの抗菌コーティングを含む)、
生殖管(膣症、膣炎、子宮頸炎、子宮内膜炎、PID)、
消化管感染(GIで開始される全身性の感染)、
中枢神経系感染、
皮膚及び皮膚組織の感染、例えば、手術部位感染、蜂巣炎及び膿瘍、二次的に感染した皮膚病、膿痂疹、及び癰又はせつ腫症(グラム陽性及びグラム陰性細菌、ブドウ球菌(staphylococcus)、例えば、MRSA、ストレプトコッカス(streptococcus)、院内(nosocomial)、創傷、熱傷を含む)を含む二次的に感染した外傷性病変(secondarily infected traumatic lesion)、筋肉の感染、関節の感染(例えば、敗血症性関節炎)、骨の感染、並びに造血系の感染、
歯根膜炎、歯肉炎を含む、口、眼、内及び外耳、並びに外耳道に関連する感染、
5b)抗ウィルス効果;
上及び下気道、
性感染疾患、
消化管感染(GIで開始される全身性の感染)、
中枢神経系感染、
5c)抗真菌効果;
上及び下気道(例えば、アフタ、皮膚粘膜カンジダ症)、
尿生殖路(例えば、外陰膣カンジダ症、亀頭炎)、
消化管感染(GIで開始される全身性の感染)、
中枢神経系感染、
皮膚及び皮膚組織の感染(例えば、皮膚粘膜カンジダ症)、皮膚病、湿疹
の予防及び治療のために好適である。
2つのクラスのラクトフェリン由来のペプチドを、設計しそして試験した。活性ペプチドを、すべてのクラスで識別した。
ヒト単球に相当するTHP‐1細胞株(TIB‐202;ATCC,Manassas,VA,USA)を、10%ウシ胎児血清(FBS;PAA Laboratories GmbH,Pasching,Austria)、1mMのピルビン酸ナトリウム(Sigma‐Aldrich,St.Louis,MO,USA)、及び20mMのHEPES(PAA,Laboratories GmbH,Pasching,Austria)を補充したRPMI1640(PAA Laboratories GmbH,Pasching,Austria)中で保持した。
5%のウマ脱線維血液(National Veterinary Institute(SVA),Uppsala,Sweden)を補充した血液寒天プレート(Columbia agar(Oxoid,Basingstoke,UK)上で培養した黄色ブドウ球菌(S.aureus)(#1800;CCUG,Gothenburg,Sweden)を、ブレインハートインフュージョン培地(3.7%のBHI;Difco,BD Diagnostics,Franklin Lakes,NJ,USA)に移し、そして37℃で一晩、250rpmで振とう機においてインキュベートした。培養物を、その後、新鮮なBHI培地で1:10に希釈し、そしてさらに2時間インキュベートして、対数増殖期に達した。細菌をペレット化し、そして600nmでの光学濃度を測定することによって推定された107細菌/mlの濃度に、1%BHI培地(超純水で100倍に希釈したBHI培地)中に懸濁した。ペプチドを、1%BHI培地において、160μM〜1,25μMまで、2倍ステップによって段階希釈した。ペプチド(100μl)を、その後、37℃で2時間、細菌(5μlの107細菌/ml)とインキュベートした。懸濁液の液滴(5μl)を、血液寒天プレートに置いた。血液寒天プレートを、37℃で一晩インキュベートした。MMC99値(すなわち、生菌の99%減少を達成するために必要な最小ペプチド濃度)を、記録した(表3)。アッセイにおいて使用した細菌懸濁液の濃度は、血液寒天プレート上の生菌数により確認した。
この第一のスクリーニングラウンド由来のペプチドに関するTNF‐α活性を、ProPHECY(商標)ソフトウェア(Saromics,Lund,Sweden)を使用して多変量解析に供した。多くの記述子を、それぞれのペプチドに関して計算した。TNF‐α活性は、その結果、これらの記述子と相関していた。独立した回帰モデルを、それぞれのペプチドクラスのために作成した。さらに、すべてのペプチドクラスを考慮したグローバルモデルをまた、作成した。回帰モデルの分析は、改善したTNF‐α活性に貢献するいくつかの変数を示唆した。第二のスクリーニングラウンドに関する新規ペプチドを、主に電荷調節、両親媒性、及び疎水性に基づいて、それぞれのペプチドクラスのために示唆した。新規設計に基づいて、約80のペプチドを、PEP screen library(Sigma)として発注し、そして抗炎症及び抗菌活性の両方について試験した。
ヒト単球に相当するTHP‐1細胞株(TIB‐202;ATCC,Manassas,VA,USA)を、10%ウシ胎児血清(FBS;PAA Laboratories GmbH,Pasching,Austria)、1mMのピルビン酸ナトリウム(Sigma‐Aldrich,St.Louis,MO,USA)、及び20mMのHEPES(PAA,Laboratories GmbH,Pasching,Austria)を補充したRPMI1640(PAA Laboratories GmbH,Pasching,Austria)中で保持した。
5%のウマ脱線維血液(National Veterinary Institute(SVA),Uppsala,Sweden)を補充した血液寒天プレート(Columbia agar(Oxoid,Basingstoke,UK)上で培養した黄色ブドウ球菌(S.aureus)(#1800;CCUG,Gothenburg,Sweden)を、ブレインハートインフュージョン培地(3.7%のBHI;Difco,BD Diagnostics,Franklin Lakes,NJ,USA)に移し、そして37℃で一晩、250rpmで振とう機においてインキュベートした。培養物を、その後、新鮮なBHI培地で1:10に希釈し、そしてさらに2時間インキュベートして、対数増殖期に達した。細菌をペレット化し、そして600nmでの光学濃度を測定することによって推定された107細菌/mlの最終濃度に、1%BHI培地(超純水で100倍に希釈したBHI培地)中に懸濁した。ペプチドを、1%BHI培地又は50%熱不活化擬似創傷滲出液(超純水で2回希釈した、生理食塩水中に0.1%のペプトン(Oxoid,Basingstoke,UK)(1つの部分)及び胎児ウシ血清(1つの部分)を含む、SWF)のいずれかにおいて、400μM〜0.78μMまで2倍ステップによって段階希釈した。ペプチド(100μl)を、その後、37℃で2時間、細菌(5μlの107細菌/ml)とインキュベートした。懸濁液の液滴(5μl)を、血液寒天プレートに置いた。血液寒天プレートを、37℃で一晩インキュベートした。MMC99値(すなわち、生菌の99%減少を達成するために必要な最小ペプチド濃度)を、記録した(表6)。アッセイにおいて使用した細菌懸濁液の濃度は、血液寒天プレート上の生菌数により確認した。
ペプチドのいくつかの変異体を、増加した電荷で設計し、そして疎水性領域を追加した。特に、両親媒性の調節は、高い活性を有するペプチドを達成するために重要であった。
ペプチド232(配列番号78)、及び220(配列番号67)の抗菌効果を、黄色ブドウ球菌(S.aureus)(CCUG1800)、MRSA(CCUG41879)、緑膿菌(P.aeruginosa)(ATCC15442)、大腸菌(CCUG31246)、化膿レンサ球菌(S.pyogenes)(CCUG4207)、P.アクネス(CCUG1794T)、表皮ブドウ球菌(S.epidermidis)(ATCC12228)、肺炎桿菌(K.pneumoniae)(ATCC13883)、A.バウマニ(A.baumannii)(ATCC19606)、及びC.アルビカンス(C.albicans)(ATCC64549)に対するMMC99(最小殺菌濃度)アッセイによって分析した。ペプチドを、BiopeptideCompany(San Diego,CA,USA)及びBachem AG(Bubendorf,Switzerland)から購入し、そして結果を、表8A及び8Bにそれぞれ示す。
ペプチド232(配列番号78)、及びペプチド220(配列番号67)のインビボ抗菌効果を、ラットの切除創傷モデルにおいて検討した。創傷を、2時間、メチシリン耐性黄色ブドウ球菌(MRSA)で接種し、続いて、細菌の終了及び収集前2時間、ペプチド又は対照(H2O)の単回投与を行った。すべてのペプチドは、顕著な抗菌効果を示した(図4)。
ペプチド232(配列番号78)、及びペプチド220(配列番号67)の抗菌効果を、ブタの皮膚のエクスビボモデルにおいて検討した。創傷を、PBS/血清 50/50の存在下、黄色ブドウ球菌(S.aureus)で接種した。接種2時間後、創傷を、ペプチド又はプラセボ(H2O)の単回投与で処理した。4時間後、処理細菌を収集し、そしてそれぞれの創傷の生菌数を測定した。結果は、局部に適用した場合、ペプチドが、非常に有効な抗感染剤であることを示すラットにおける知見を裏付けた(図5)。
Claims (7)
- 請求項1に記載のペプチドを含む、医薬組成物。
- 感染症、炎症、創傷、及び瘢痕の治療及び/又は予防で使用するための、請求項2に記載の医薬組成物。
- 感染症の治療及び/又は予防で使用するための、請求項3に記載の医薬組成物。
- 炎症の治療及び/又は予防で使用するための、請求項3に記載の医薬組成物。
- 前記感染症が、皮膚及び皮膚組織感染症である、請求項4に記載の医薬組成物。
- 膿痂疹、火傷、感染した擦過傷、感染した裂傷、擦傷、丹毒、蜂巣炎、膿瘍、フルンケル、癰、閉鎖創、手術部位感染、二次的に感染した皮膚炎:アトピー性皮膚炎、乾癬、及びアレルギー性接触皮膚炎、動物咬傷、並びにカテーテル関連感染の治療、予防法(prophylaxis)及び/又は予防で使用するための、請求項3に記載の医薬組成物。
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EP11152213A EP2481751A1 (en) | 2011-01-26 | 2011-01-26 | Human lactoferrin derived peptides |
EP11152213.2 | 2011-01-26 | ||
PCT/EP2012/051111 WO2012101156A2 (en) | 2011-01-26 | 2012-01-25 | New synthetic peptides and their use |
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JP2013550865A Expired - Fee Related JP6158713B2 (ja) | 2011-01-26 | 2012-01-25 | ヒトラクトフェリン由来ペプチド及びその使用 |
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US (2) | US9132165B2 (ja) |
EP (3) | EP2481751A1 (ja) |
JP (2) | JP6158713B2 (ja) |
KR (2) | KR101933900B1 (ja) |
CN (2) | CN103459419B (ja) |
AU (2) | AU2012210565B2 (ja) |
BR (2) | BR112013018365A2 (ja) |
CA (2) | CA2825246A1 (ja) |
ES (2) | ES2633353T3 (ja) |
MX (2) | MX341020B (ja) |
PL (1) | PL2668205T3 (ja) |
RU (2) | RU2596393C2 (ja) |
WO (2) | WO2012101156A2 (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2481751A1 (en) * | 2011-01-26 | 2012-08-01 | PharmaSurgics in Sweden AB | Human lactoferrin derived peptides |
GB201401877D0 (en) * | 2014-02-04 | 2014-03-19 | Univ Tromsoe | Peptides |
CN104888202A (zh) * | 2014-05-22 | 2015-09-09 | 闫牧乔 | 一种治疗扁桃体炎的药物 |
IT201800002457A1 (it) * | 2018-02-07 | 2019-08-07 | Neilos S R L | Composizione per la prevenzione e il trattamento delle affezioni delle vie respiratorie |
RU2681216C1 (ru) * | 2018-09-05 | 2019-03-05 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Способ стимуляции регенерации инфицированных ран кожи и мягких тканей с применением пептида Gly-His-Lys-D-Ala |
RU2681310C1 (ru) * | 2018-09-05 | 2019-03-06 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Способ первичной хирургической обработки инфицированных ран кожи и мягких тканей с использованием пептида Gly-His-Lys-D-Ala |
KR102032945B1 (ko) * | 2018-12-03 | 2019-10-16 | 순천대학교 산학협력단 | 항염증 활성을 나타내는 펩타이드 및 이를 유효성분으로 포함하는 항염증용 조성물 |
NL2024839B1 (en) * | 2020-02-05 | 2021-09-13 | Cbmr Scient Nanoscience B V | Antimicrobial peptide for treatment and controlling skin disorders relating to microbial infection |
Family Cites Families (25)
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---|---|---|---|---|
JP2818056B2 (ja) | 1990-09-07 | 1998-10-30 | 森永乳業株式会社 | 抗菌性ペプチドおよび抗菌剤 |
US5656591A (en) | 1992-01-23 | 1997-08-12 | Morinaga Milk Industry Co., Ltd. | Antimicrobial agents and method for treating products therewith |
JP3347819B2 (ja) | 1993-06-28 | 2002-11-20 | 森永乳業株式会社 | 抗菌性ペプチドの精製方法 |
US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
JP3529423B2 (ja) | 1994-04-01 | 2004-05-24 | 森永乳業株式会社 | 抗菌性ペプチドの製造方法 |
JP3812957B2 (ja) | 1994-08-02 | 2006-08-23 | 森永乳業株式会社 | 角膜損傷治療剤 |
JPH08143468A (ja) | 1994-11-17 | 1996-06-04 | Morinaga Milk Ind Co Ltd | 抗潰瘍剤 |
JP2001504447A (ja) | 1996-08-12 | 2001-04-03 | エイプラス サイエンス インベスト アーベー | ラクトフェリンおよび/またはラクトフェリシンでの、感染、炎症および/または腫瘍の処置および予防 |
US6696545B1 (en) * | 1997-04-11 | 2004-02-24 | Sangstat Medical Corporation | Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation |
SE9804614A0 (en) | 1998-07-06 | 2000-01-07 | A+ Science Invest Ab | New peptides and use thereof |
US6399570B1 (en) | 1999-02-05 | 2002-06-04 | Agennix, Inc. | Antimicrobial/endotoxin neutralizing polypeptide |
IL146130A0 (en) * | 1999-05-14 | 2002-07-25 | Univ California | Anti-inflammatory therapy for inflammatory mideated infection |
WO2001034641A2 (en) | 1999-11-11 | 2001-05-17 | Am-Pharma B.V. | Antimicrobial activity of the first cationic cluster of human lactoferrin |
RU2165769C1 (ru) * | 2000-07-13 | 2001-04-27 | Якубовская Раиса Ивановна | Антибактериальный, антиоксидантный, иммуномодулирующий и антиканцерогенный препарат и способ его применения |
SE0102067D0 (sv) | 2001-06-11 | 2001-06-11 | A & Science Invest Ab | Prevention of neovascularization of intervertebral discs and/or of tissues with local inflammation |
WO2006047744A2 (en) | 2004-10-26 | 2006-05-04 | Agennix Incorporated | Compositions of lactoferrin related peptides and uses thereof |
WO2008006125A1 (en) * | 2006-07-10 | 2008-01-17 | Österreichische Akademie der Wissenschaften | Antimicrobial peptides |
JP5384948B2 (ja) * | 2007-02-09 | 2014-01-08 | ジェノミディア株式会社 | 新規ポリペプチド及びそれを有効成分として含有する抗菌剤 |
JP5444544B2 (ja) * | 2007-02-09 | 2014-03-19 | ジェノミディア株式会社 | 血管新生誘導剤及びそれに用いられるポリペプチド |
EP2050461A1 (en) | 2007-10-19 | 2009-04-22 | PharmaSurgics in Sweden AB | Peptides based on the sequence of human lactoferrin and their use |
EP2060586A1 (en) * | 2007-11-14 | 2009-05-20 | PharmaSurgics in Sweden AB | New synthetic arginine substituted peptides and their use |
CN101809029B (zh) * | 2008-05-23 | 2016-06-15 | 第一三共株式会社 | 具有延长目标肽的血浆半衰期作用的肽 |
PL2387390T3 (pl) * | 2009-01-13 | 2013-12-31 | Pergamum Ab | Zawierające kwas hialuronowy kompozycje do leczenia ran, blizn oraz zrostów powstających po zabiegach chirurgicznych |
EP2481751A1 (en) * | 2011-01-26 | 2012-08-01 | PharmaSurgics in Sweden AB | Human lactoferrin derived peptides |
KR101341210B1 (ko) * | 2013-01-24 | 2013-12-12 | 재단법인 지능형 바이오 시스템 설계 및 합성 연구단 | 신규한 항균 펩타이드 및 이의 용도 |
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2011
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- 2012-01-25 MX MX2013007995A patent/MX341020B/es active IP Right Grant
- 2012-01-25 RU RU2013139302/04A patent/RU2593757C2/ru active
- 2012-01-25 ES ES12701866.1T patent/ES2633353T3/es active Active
- 2012-01-25 AU AU2012210565A patent/AU2012210565B2/en not_active Expired - Fee Related
- 2012-01-25 CA CA2825246A patent/CA2825246A1/en not_active Abandoned
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- 2012-01-25 JP JP2013550865A patent/JP6158713B2/ja not_active Expired - Fee Related
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