TW201339176A - 短抗微生物脂肽 - Google Patents
短抗微生物脂肽 Download PDFInfo
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- TW201339176A TW201339176A TW102109748A TW102109748A TW201339176A TW 201339176 A TW201339176 A TW 201339176A TW 102109748 A TW102109748 A TW 102109748A TW 102109748 A TW102109748 A TW 102109748A TW 201339176 A TW201339176 A TW 201339176A
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Abstract
本發明揭示具有生物活性及治療活性之肽。具體而言，本發明揭示展現抗微生物活性之KPV或KdPT之脂化二肽或三肽類似物。具體而言，本發明之該等肽提供比基礎三肽離胺酸-脯胺酸-纈胺酸及離胺酸-d-脯胺酸-酪胺酸更加強之抗微生物活性。所揭示之肽具有通式C12-18脂質-KXZ-NH2，其中K係離胺酸；X係脯胺酸、d-脯胺酸、組胺酸或精胺酸；Z可視需要選用且若存在則Z係纈胺酸、蘇胺酸、丙胺酸或白胺酸；且末端COOH經NH2醯胺化。該C12-18脂質較佳係月桂酸(C12)、肉豆蔻酸(C14)、十五碳酸(C15)、棕櫚酸(C16)或硬脂酸(C18)之脂質部分。本發明進一步關於使用該等肽來治療侵襲皮膚及其他相關黏膜體表(例如口腔)之多種損傷、發炎或細菌感染之方法。
Description
本申請案主張對2012年3月20日提出申請的美國臨時申請案第61/613,212號之優先權益，該臨時申請案之全文以引用方式併入本文中。
本發明係關於具有生物活性及治療活性之肽。具體而言，本發明係關於展現抗微生物活性之KPV或KdPT之脂化二肽或三肽類似物。具體而言，本發明之肽提供強於基礎三肽離胺酸-脯胺酸-纈胺酸及離胺酸-d-脯胺酸-酪胺酸之抗微生物活性。本發明進一步關於使用該等肽來治療侵襲皮膚及其他相關體表(例如口腔)之多種損傷、發炎或細菌感染之方法。
數十年來研究者一直致力於研發抗微生物治療及試劑。最近，需要新穎抗微生物劑來治療數目漸增之耐藥性細菌、病毒及真菌感染。
在科學文獻及已頒佈專利二者中已報導多種生物活性肽。肽在歷史上係自天然來源分離，且最近已成為結構-功能關係研究之對象。此外，天然肽已充當設計合成肽類似物之起點。
有多個專利闡述了含有短肽之化妝品組合物。例如，美國專利第6,492,326號提出製備並使用含有五肽及皮膚護理活性成份之皮膚護理組合物。
Strom等人2003(Journal of Medicinal Chemistry 46：1567-1570)闡述含有化學修飾之抗細菌短肽，主要是極短肽(二聚體及三聚體)。亦闡述了某些六肽。然而，並未測試或論述該等六肽之抗微生物活性。
α-激黑細胞素(α-MSH)係具有有效抗發炎活性之13-胺基酸神經肽。其係藉由較大前驅物分子前嗎啡黑皮質素(pre-opiomelanocortin)之翻譯後處理來產生。已證實α-MSH之羧基末端三肽(包括殘基11至13)KPV在活體內及活體外發揮抗發炎活性(Brzoska,T.、Luger,TA.等人，α-melanocyte-stimulating hormone and related tripeptides：biochemistry,anti-inflammatory and protective effects in vitro and in vivo,and future perspectives for the treatment of immune-mediated inflammatory diseases.Endocrine Reviews 2009.29(5)：581-602)。已闡述結構相關衍生物KdPT(KPT)與IL-1β之殘基193-195共線且似乎能夠與IL-1 I型受體相互作用(Luger T.A.及Brzoska T.α-MSH related peptides：a new class of anti-inflammatory and immunomodulating drugs.Ann Rheum Dis 2007；66(增刊III)：iii52-iii55)。有一篇報導提出，KPV對金黃色葡萄球菌(S.aureus)及白色念珠菌(C.albicans)具有抗微生物影響但並未測得MIC(Cutuli M等人，2000,antimicrobial effects of α-MSH peptides,J.Leukocyte Biology,67：233-239)。與KPV不同，從未報導KdPT三肽具有抗微生物影響。
因此，業內需要研發具有針對眾多微生物(包含革蘭氏(gram)陰性及革蘭氏陽性細菌)之寬範圍有效抗微生物活性之肽。抗微生物肽之製造成本對醫藥及化妝品應用而言亦係關鍵考慮因素。本發明揭示可在醫藥或化妝品組合物中用於局部治療或管控與細菌及真菌感染相關之皮膚病況之成本有效的抗微生物短肽。
本發明係關於展現抗微生物活性之KPV或KdPT之脂化二肽或三
肽類似物。具體而言，本發明之肽提供強於基礎三肽離胺酸-脯胺酸-纈胺酸及離胺酸-d脯胺酸-酪胺酸之抗微生物活性。經分離肽之目標抗細菌活性係針對彼等侵襲皮膚及相關黏膜表面之細菌。儘管不欲受限於任何具體機制，但本發明肽能夠藉由抑制細菌生長及抑制與細菌感染相關之發炎來促進皮膚健康。
本發明之一實施例係關於以下通式之脂化二肽或三肽：C12-18脂質-KXZ-NH2，其中K係離胺酸；X係脯胺酸、D-脯胺酸(脯胺酸之D-異構物)、組胺酸或精胺酸；Z可視需要選用，且若存在則Z係纈胺酸、蘇胺酸、丙胺酸或白胺酸；且末端COOH經NH2醯胺化。該肽係經C12-18脂質脂化且較佳係經以下酸之脂質部分：月桂酸(C12)、肉豆蔻酸(C14)、十五碳酸(C15)、棕櫚酸(C16)或硬脂酸(C18)。十五碳醯基及棕櫚醯基係最佳脂質基團。
較佳脂化二胺基酸及三胺基酸包含C12-18脂質-離胺酸-脯胺酸-纈胺酸-NH2；C12-18脂質-離胺酸-d-脯胺酸-蘇胺酸-NH2；C12-18脂質-離胺酸-脯胺酸-丙胺酸-NH2；C12-18脂質-離胺酸-脯胺酸-白胺酸-NH2；C12-18脂質-離胺酸-脯胺酸-NH2；C12-18脂質-離胺酸-d-脯胺酸-NH2；C12-18脂質-離胺酸-組胺酸-NH2；及C12-18脂質-離胺酸-精胺酸-NH2。
本發明之另一實施例係關於含有醫藥上或化妝品上可接受之載劑及一或多種上述肽之組合物。該等組合物中之肽濃度較佳介於約0.1 μg/mL至約20 μg/mL或約0.1 μg/mL至約10%(w/v)範圍內。適於局部施用之較佳組合物形式係氣溶膠、乳液、液體、水溶液、洗劑、乳
霜、糊劑、軟膏、粉劑及發泡體。
本發明亦係關於使用上述組合物來治療或預防哺乳動物皮膚之微生物感染之方法。通常，治療方法需要向皮膚(表皮)及相關黏膜組織之受侵襲區域投與有效量之含肽組合物且保持有效時間長度。在細菌感染係由選自痤瘡丙酸桿菌(P.acnes)、金黃色葡萄球菌、大腸桿菌(E.coli)及白色念珠菌之細菌引起時亦可使用該等方法。
此外，本發明之肽及含有該等肽之組合物可提供納入一般皮膚護理及化妝品調配物(例如各種皮膚化妝品、皮膚乳霜、洗劑、防曬劑及治療性洗劑或乳霜(例如抗痤瘡調配物))中之有用特徵。
為更充分理解本文所闡述之本發明，進行以下詳細描述。本發明概言之係關於包括以下通式之KPV或KdPT之抗微生物脂化二肽或三肽類似物之組合物及方法：C12-18脂質-KXZ-NH2，其中K係離胺酸；X係脯胺酸、d-脯胺酸、組胺酸或精胺酸；Z可視需要選用，且若存在則Z係纈胺酸、蘇胺酸、丙胺酸或白胺酸；且末端COOH經NH2醯胺化。
可用來提供本發明化合物之C12-18脂質組份之飽和或不飽和脂肪酸之實例包含：
α-激黑細胞素(α-MSH)係具有有效抗發炎活性之13-胺基酸神經肽。其係藉由較大前驅物分子前嗎啡黑皮質素之翻譯後處理來產生。已證實α-MSH之羧基末端三肽(包括殘基11至13)KPV在活體內及活體外發揮抗發炎活性(Brzoska,T.、Luger,TA.等人，α-melanocyte-stimulating hormone and related tripeptides： biochemistry, anti-inflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases.Endocrine reviews 2009.29(5)：581-602)。已闡述結構相關衍生物KdPT(KPT)與IL-1β之殘基193-195共線且似乎能夠與IL-1 I型受體相互作用(Luger T.A.及Brzoska T.α-MSH related peptides：a new class of anti-inflammatory and immunomodulating drugs.Ann Rheum Dis 2007；66(增刊III)：iii52-iii55)。有一篇報導提出，KPV對金黃色葡萄球菌及白色念珠菌具有抗微生物影響但並未測得MIC(Cutuli M等人，2000,antimicrobial effects of α-MSH peptides,J.Leukocyte Biology,67：233-239)。與KPV不同，從未報導KdPT三肽具有抗微生物影響。
使用CLSI(Clinical and Laboratory standard Institute)推薦之標準方案(Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically；Approved Standard-第9版)來測定抗微生物劑之最低抑制濃度(MIC)。令人驚奇地係，KPV與KdPT在最高
2000 μg/ml濃度下皆不顯示針對大腸桿菌、金黃色葡萄球菌或酵母菌之可檢測MIC。該較差抗微生物特徵使得兩種三肽極不適合用於需要抗微生物活性之治療或化妝品應用中。
藉助用不同長度之脂質對KPV及KdPT之α胺基實施N末端乙醯化來修飾兩種肽。該修飾產生具有針對廣譜微生物之新穎、優良且出乎意料的抗微生物活性之分子。所得脂三肽顯示顯著優於母體肽之抵抗革蘭氏陰性及革蘭氏陽性細菌及酵母菌之抗微生物活性。脂質長度亦影響該活性且發現，碳數目介於12至18範圍內之脂質最有效。脂化後，MIC在Muller Hinton培養液中顯著改良，針對痤瘡丙酸桿菌、金黃色葡萄球菌、大腸桿菌及白色念珠菌之MIC介於1 μg/ml至64 μg/ml範圍內。用A或L替代Pal-KPV-NH2中之第三殘基保留抗微生物活性且此發現促使自KPV或KdPT移除第三胺基酸殘基。所得脂二肽Pal-KP-NH2、Pal-K-dP-NH2皆顯示新穎抗微生物活性。此外，KP-NH2與KdP-NH2二者在人類皮膚角質細胞中針對組胺誘導之IL-6表現顯示中等抗發炎活性(數據未顯示)。進一步用V、A、F、G、S、H、K、I、L、D、R、S、W或Y取代第二殘基P或dP。此工作提供一組具有從未報導過之新穎抗微生物活性之脂二肽。在醫藥或化妝品製劑中可將該抗微生物活性轉變成治療應用。
總而言之，本發明係基於以下發現：衍生自KPV之特定脂二肽及脂三肽，其係由脂質-KXZ組成，其中脂質可合意地選自棕櫚醯基-、月桂醯基-、肉豆蔻醯基-、十五碳醯基及硬脂醯基-；且x可選自呈L-或D-鏡像異構形式之P、G、I、H及R，Z可視需要選用且若存在則Z係羧基末端醯胺化之V、T、A或L。該等短脂肽係針對包含以下之革蘭氏陽性及革蘭氏陰性細菌之新穎抗微生物劑：大腸桿菌(E.coli)、金黃色葡萄球菌(S.aureus)、痤瘡丙酸桿菌(P.acnes)、皮癬菌(dermatophyte，例如發癬菌(Trichophyton spp.))及酵母菌念珠菌
(Candida spp.，包含白色念珠菌、光滑念珠菌(C.glabrata)及熱帶念珠菌(C.tropicalis))。
縮寫關鍵詞：以上所列示之脂質係使用標準肽化學經由醯胺鍵與二肽或三肽偶合：myr=肉豆蔻酸，pen=十五碳酸，pal=棕櫚酸，ste=硬脂酸，lau=月桂酸。胺基酸之右旋形式縮寫成「d」，例如脯胺酸之右旋形式係d-脯胺酸。此外，胺基酸之縮寫遵循習用用法：
用於醫藥調配及投與之技術之細節可參見最新版的Remington’s Pharmaceutical Sciences(Mack Publishing公司，Easton Pa.)。儘管希望經由局部表面遞送，但仍有其他遞送方式，例如：經口、非經腸、
氣溶膠、肌內、皮下、經皮、髓內、鞘內、心室內、靜脈內、腹膜內或鼻內投與。本發明可於多種載劑媒劑中調配，例如噴霧劑；氣溶膠；水包油型乳液；油包水型乳液；面霜或身體乳霜；防曬洗劑或曬後洗劑；或其他局部投與媒劑。此外，本發明之肽及含有該等肽之組合物可提供有用特色，供納入一般皮膚護理及化妝品調配物(例如各種皮膚化妝品、皮膚乳霜、洗劑、防曬劑及治療性洗劑或乳霜(例如抗痤瘡調配物))中。
如本文所使用，術語「治療劑」意指用於治療、抵抗、改善、預防或改良患者之不期望病況或疾病之製劑。本發明所治療病況包括多種通常侵襲諸如人類等哺乳動物之皮膚或黏膜區域之細菌感染。該等方法亦適用於由選自痤瘡丙酸桿菌、金黃色葡萄球菌、大腸桿菌及白色念珠菌之細菌或真菌所引起之細菌感染。
根據所涵蓋之具體應用，可將本發明所提供之醫藥組合物調配成溶液、懸浮液、非經腸式製劑、軟膏、乳霜、洗劑、噴霧劑、粉劑或錠劑膠囊。非經腸式製劑可包含媒劑，例如經過特別蒸餾之無熱原水、磷酸鹽緩衝液或生理食鹽水。軟膏、乳霜、洗劑及噴霧劑可包含諸如植物油或礦物油、白石蠟脂或高分子量(即大於C12)醇等載劑。錠劑或膠囊可包含稀釋劑(例如乳糖)、黏合劑、潤滑劑(例如硬脂酸)及崩解劑(例如玉米澱粉)。
含有有效量活性劑之口用噴霧劑亦可使用一或多種本發明脂化肽調配。可將此材料作為抗微生物劑，每天在牙齒及牙齦表面之各四分象限上噴霧0.25 ml至0.5 ml份量1次至3次。在假牙佩戴者之情形下，可每天帶上假牙之前將噴霧劑直接用於假牙表面。若需要，可提供含有有效量抗微生物劑之漱口水調配物。
本發明組合物亦可包含醫藥上或皮膚病學上可接受之載劑。載劑之實例包含乳液及凝膠。乳液通常係油相與水相之混合物。組合物
亦可包括磨砂膏(exfoliant abrasive)材料。組合物亦可包括穩定劑。組合物亦可包括控泡化合物。
組合物亦可包含一或多種其他皮膚護理活性組份。皮膚護理活性組份之實例包含脫屑活性物質、抗痤瘡活性物質、維生素B3化合物、類視色素(包含視黃醇、視黃醛、視黃醇酯、視黃醇丙酸酯、視黃酸及視黃醇棕櫚酸酯)、羥酸、自由基捕獲劑、螯合劑、抗發炎劑、局部麻醉劑、仿曬活性物質(tanning active)、亮膚劑、溶脂劑、類黃酮、抗微生物活性物質、皮膚癒合劑、抗真菌活性物質、菌綠烯醇(farnesol)、植烷三醇、尿囊素、水楊酸、菸醯胺、右泛醇、生育酚乙酸酯及葡糖胺。
組合物亦可包含防曬劑化合物。防曬劑化合物之實例包含無機防曬劑化合物及有機防曬劑化合物。無機防曬劑化合物可包含金屬氧化物，例如氧化鋅、氧化鈦及氧化鐵。有機防曬劑化合物可包含甲氧基肉桂酸辛基酯、水楊酸辛基酯、對苯二亞甲基二樟腦磺酸、阿伏苯宗(avobenzone)及奧克立林(octocrylene)。
1.肽合成. 所有所揭示之肽皆係使用標準Fmoc(9-茀基甲氧基羰基)固相化學來合成。該等肽係使用標準胺基酸製備為醯胺化或游離酸序列。
2.細菌菌株及培養條件. 此研究中所包含之細菌菌株列示於表1中。除非另外指明，否則使大腸桿菌UB1005、金黃色葡萄球菌SAP0017(MRSA)及白色念珠菌105在37℃下於Mueller Hinton(MH)(Difco,BD Biosciences,MD)瓊脂板及培養液(每公升含2 g牛肉膏、17.5 g酸水解酪蛋白及1.5 g澱粉)中生長。在敏感性測試之前將來自冷凍原液之細菌於剛製成之MH瓊脂板上繼代培養。對於痤瘡丙酸桿菌，使細菌在37℃下在使用厭氧罐及AnaeroGenTM(Oxoid,Basingstoke,Hampshire,England)產生之厭氧條件中於BBLTM腦心浸液
(Becton,Dickinson & Company，Sparks MD)培養液或瓊脂板中生長。
3.抗微生物活性之測定. 使用經改良CLSI微量滴定培養液稀釋分析(Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically；Approved Standard-第9版)來測定每一肽之最低抑制濃度(MIC)。使用105-106個菌落形成單位(CFU)/ml或104 CFU/ml(對於酵母菌)之接種物。以在37℃下培育15 h至20 h後大於90%之微生物生長被抑制之最低肽濃度作為MIC值。對於痤瘡丙酸桿菌，在測定MIC之前，將其在37℃下在厭氧條件下培育2周。使用給定濃度(約2-5倍MIC)之混合有指示劑微生物之肽實施殺菌動力學。適當稀釋後，在規定時間間隔後將細胞平鋪於瓊脂板上且在37℃下培育過夜。在痤瘡丙酸桿菌之情形下，需要延長培育時間段。計數CFU且繪製成經肽治療後細菌隨時間之存活率，此指示肽殺死微生物之有效性。
4.皮膚組織毒性測定. 皮膚毒性及相容性係使用EpiDerm(EPI-200)皮膚組織及MTT套組(MTT-100)(MatTek,Ashland,MA)根據製造商說明書來測定。分別使用1% Triton X-100及PBS作為陽性(有毒)及陰性(無毒)對照。
5.基因剖析分析. 使用由Sunny Biodiscovery公司(Santa Paula,CA)實施之PCR陣列分析人類真皮成纖維細胞中之84個編碼細胞外基質黏附分子之基因。人類真皮成纖維細胞係來自Zen-Bio,Research Triangle Park,NC(目錄編號為DF-F，批號為DFMF112410)。使細胞(低傳代)在DMEM/10%FCS w/o酚紅中生長直至其達到鋪滿期，此後將其以一式兩份與3 μg/ml、5 μg/ml或10 μg/ml測試材料或水一起培育24 h。培育結束時，在Nikon TS倒置顯微鏡下觀察細胞。未發現實驗條件有細胞毒性。定性評價顯示，在5 μg/ml測試材料下經受有絲分裂之細胞多於在10 μg/ml測試材料下，且因此選擇5 μg/ml條件用於
RNA提取。
在培育時間段結束時，將細胞保存在RNAlater溶液(Ambion,Austin,TX)中並保持6 h。用來自Machery-Nagel,Bethleem,PA之NucleoSpin RNA II套組提取且純化RNA。用Agilent HP-8452A二極管陣列分光光度計在230 nm、260 nm及280 nm下評價所純化總RNA。均衡各樣品之RNA濃度且使用來自Qiagen(前SA Biosciences)之使用PCR陣列PAHS-013A(www.sabiosciences.com/rt_pcr_product/HTML/PAHS-013A.html)與第一鏈合成(1st strand synthesis)套組、SYBR Green主混合物及PCR運行條件之BioRad iCycler iQ檢測系統藉由實時定量PCR來量測所關注基因之表現。在用RT2剖析儀PCR陣列數據分析3.5版軟體將基因表現正規化至所攜載之5個管家基因後，使用效率△△Ct方法來量化結果。
KPV三肽與KdPT三肽二者在活體外及活體內之抗發炎活性皆為人所知。亦已報導在磷酸鹽緩衝液中KPV三肽具有針對金黃色葡萄球菌及白色念珠菌之抗微生物活性(Cutulis M.等人，Antimicrobial effects of α-MSH peptides.J.Leukocyte Bio.2000 67：233-239)。然而，從未測定或報導過KPV之MIC值。亦未知KdPT是否具有抗微生物影響。
使用CLSI推薦之微量培養液稀釋分析(用於在活體外測定抗生素及抗真菌劑之MIC之標準分析)在培養基中測試KPV及K-dPT之抗微生物活性(Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically；Approved Standard-第9版)。令人驚奇地係，在MH培養液中，具有或不具有C末端醯胺化之KPV(HB2067、HB2068)與KdPT(HB2089、HB2090)二者在最高為2000 μg/ml之濃度下皆不顯示可檢測MIC(表1)。此與Rauch及合作者所闡
述之發現一致，即使用針對白色念珠菌菌株SC5314(用於抗真菌敏感性實驗之標準實驗室菌株)之生長分析顯示，KPV在最高100 μM下不能抑制酵母菌生長(Rauch I.、Holzmeister S.及Kofler B.Anti-Candida activity of alpha-melanocyte-stimulating hormone(alpha-MSK)peptides.J.Leukoc.Biol.2009.85(3)：371-372)。
用不同長度之脂質修飾KPV及KdPT，此旨在尋找抗微生物特徵優於母體三肽或相對於其經改良之類似物。三肽核心之乙醯化揭露驚人結果。脂質長度似乎至關重要且表2顯示使用KPV作為實例之結果。
碳數目介於11至18範圍內之脂質似乎對KPV及KdPT之抗微生物活性具有正面影響(表1、表2)。對於KPV及KdPT，最佳脂質長度確定為15及16個碳(表1、表2)。該等脂質顯著增強兩種肽針對廣譜微生物(包含革蘭氏陽性、革蘭氏陰性細菌及酵母菌)之抗微生物活性，如SEQ ID NO 5(HB2178)、7或24(HB2180或HB2200)、17(HB2192)、23(HB2199)所證實(表1、表2)。實際上，與在最高2000 ug/ml下無活性之單獨母體三肽KPV-NH2或KdPT-NH2相比，脂肽針對痤瘡丙酸桿菌、金黃色葡萄球菌、大腸桿菌及白色念珠菌之MIC顯示接近2000倍的改良，其介於1-64 μg/ml範圍內(表1)。將脂質長度增加至18-碳消除了革蘭氏陰性選擇性活性，但保留了革蘭氏陽性及酵母菌選擇性活性二者(表1、表2)。進一步用A或L取代Pal-KPV-NH2中之第三胺基酸以獲得SEQ ID NO 30(HB2208)及31(HB2209)。令人感興趣的是，SEQ ID NO 30與31二者皆維持適宜廣譜抗微生物活性，從而表明，所觀察到之新穎抗微生物活性可能需要或可能不需要Pal-KPV-NH2中之第三殘基V。除了其如藉由MIC指示之廣譜活性外，包含SEQ ID NO 5(HB2178)、7(2180)、30(HB2208)及31(HB2209)在內之類似物在殺菌分析中皆具有殺菌性且在20 min內消滅5-6 log之金黃色葡萄球菌
(表3)。總而言之，碳數目介於12至18範圍內之脂質附接至KPV-NH2或KdPT-NH2可產生具有先前從未報導過之新穎廣譜抗微生物活性之脂三肽。Pal-KPV-NH2或Pal-KdPT-NH2中之第三殘基對於所觀察到之新穎抗微生物活性而言可能關鍵或可能不關鍵。由於諸如HB2184及HB2182等未醯胺化對應部分之活性較低或無活性，因此C末端醯胺化對於所闡述之抗微生物活性極為關鍵。
用A及L取代Pal-KPV-NH2中之第三殘基未消除活性促使進行進一步修飾。因此，移除Pal-KPV-NH2及Pal-KdPT-NH2二者之第三胺基酸殘基以獲得脂二肽SEQ ID NO 26(HB2202)及SEQ ID NO 27(HB2203)。兩種衍生物顯示與母體脂三肽Pal-KPV-NH2及Pal-KdPT-NH2相似之新穎抗微生物活性(表1)。該活性出人意料且從未被揭示。殺菌動力學表明，兩種脂二肽衍生物在PBS中具有同等殺菌性且在20 min之直接接觸內消滅超過5 log之包含痤瘡丙酸桿菌、金黃色葡萄球菌、大腸桿菌及酵母菌白色念珠菌在內之微生物(表3)。本發明所闡述脂二肽之抗微生物活性亦表現為兩種脂二肽在10%胎牛血清存在下皆維持針對金黃色葡萄球菌之顯著殺菌活性(表3)。此尤其顯著。肽抗生素通常因干擾且結合宿主蛋白從而導致抗微生物活性降低而引起問題。慮及皮膚切口或損傷(包含痤瘡損傷)通常伴隨受傷區域之血清浸潤，在血清中之抗微生物活性對於潛在治療而言非常重要。
為證實Pal-KP-NH2含有最佳活性設計，交換P與K之位置，以產生HB2251(Pal-PK-NH2)及HB2255(Pal-PK-OH)。與Pal-KP-NH2相比，Pal-PK-NH2顯示活性降低超過8倍。未醯胺化衍生物Pal-PK-OH及Pal-KP-OH無活性，再次表示C末端醯胺化對於抗微生物活性至關重要。
使用EpiDermTM皮膚模型(MatTek,Ashland,MA)與改良MTT分析法之組合來測試脂二肽產生皮膚刺激性之可能性。EpiDermTM皮膚模
型展現均勻且高度可再現之類似活體內形態及生長特徵。EpiDermTM係由類似彼等活體內所發現之組織性基底層、棘層、顆粒層及角質化層組成。將該等組織用期望濃度之每一化合物處理20 hr。如表1中所見，由HB2202、HB2203、HB2180、HB2208及HB2209代表之所選脂肽在高達2000 μg/ml下皆未對組織活力展現負面效應。
受新穎脂二肽HB2202及HB2203之鼓勵，再用V、A、F、G、L、S、H、K、I、S、R、T、Y或W替代Pal-KP-NH2及Pal-K-dP-NH2之第二殘基來進一步修飾。如表1中所顯示，該修飾法使得進一步發現一組新穎脂二肽，其具有廣譜抗微生物活性(Pal-KH-NH2、Pal-KR-NH2、Pal-KR-OH)或更強之革蘭氏陽性選擇性活性(Pal-KG-NH2、Pal-KL-NH2及Pal-KI-NH2)(表1)。
選擇三種代表性化合物SEQ ID NO.26(HB2202)、SEQ ID NO.41(HB2242)及SEQ ID NO.55(HB2259)對人類真皮成纖維細胞進行基因剖析研究。如表4中所顯示，該三種化合物在對人類真皮成纖維細胞之影響方面顯示相似傾向/模式。受影響之基因係彼等參與傷口癒合及抗纖維化級聯作用者。該三種化合物對整合素之影響顯示在：HB2202及HB2242上調ITGA2(整合素α 2)表現，而HB2259誘導ITGA6(整合素α 6)(表4)。整合素與膠原蛋白結合，且在細胞與基質之相互作用中扮演重要角色。該等蛋白質在完整皮膚中係由基底角質細胞大量表現，且為人類皮膚傷口之上皮再生所必需。該等化合物亦調節ADAMTS(具有1型凝血酶敏感蛋白之adam金屬肽酶)及THBS3(凝血酶敏感蛋白)之表現(表4)，該兩種蛋白皆參與傷口癒合。在動物模型研究中，在THBS基因剔除小鼠中，下調凝血酶敏感蛋白時，與對照小鼠相比，顯示會在缺血後促進動脈生成、血管生成及血流恢復(Kyriakides TR及MacLauchlan S.The role of thrombospondins in wound healing,ischemia,and the foreign body reaction.J Cell Commun
Signal 2009.3：215-225)。表4中亦顯示，所有三種化合物皆顯著下調CTGF(結締組織生長因子)以及CTNND1(連環蛋白)之表現。CTGF與CTNND1皆與纖維增生活性相關，且已發現在諸如瘢痕瘤及肥厚性瘢痕(HTS)等病症中之表現量升高(Poon R等人，Catenin driven neoplastic and reactive fibroproliferative disorders.PLoS One.2012；7：e37940)。HTS代表傷口癒合之基本過程中之畸變，從而使成纖維細胞產生過量膠原蛋白。燒傷、創傷性損傷及手術程序通常引起HTS。在用抗微生物劑消除諸如細菌及真菌等感染物後，傷口感染亦使皮膚留下HTS。脂二肽亦影響KAL1(表4)。此因已發現由KAL1基因編碼之蛋白質在異位性皮炎中參與調節表皮神經密度而尤其令人感興趣。KAL1過表現抑制軸突過度生長，從而可抑制異位性皮炎中之神經支配過強及異常搔癢感(Tengara S等人，Keratinocyte-derived anosmin-1,an extracellular glycoprotein encoded by the X-linked Kallmann syndrome gene,is involved in modulation of epidermal nerve density in atopic dermatitis.J Dermatol Sci 2010.58：64-71)。總之，除所論述之廣譜抗微生物活性外，短脂肽可活化人類真皮細胞以促進傷口癒合及抗纖維化活性。因此，該等脂肽有益於抗微生物治療後之傷口恢復。
本發明包含下列實例以展示本發明之某些較佳實施例。
傷口感染係因多重抗藥性病原體(如MRSA)之頻率增加而加重之顯著問題。本發明可在治療上或化妝品上用於治療、改良且預防細菌相關皮膚病況(包含痤瘡、異位性皮炎、酒渣鼻)或真菌相關皮膚病況(包含頭皮屑及足癬)。
金黃色葡萄球菌係醫院獲得性感染之主要原因，最常與血流、皮膚及軟組織、呼吸機輔助肺炎及導管相關。由耐甲氧西林(methicillin)金黃色葡萄球菌(MRSA)引起之感染頻率增加尤其引人關注，尤其在美國在加護病房中患病率大於55%，且該發病率導致較長住院時間、較高成本及較高死亡風險。基因型與HA-MRSA不同之社區獲得性MRSA(CA-MRSA)在無傳統風險因子之患者中現亦已成為確立的威脅。除金黃色葡萄球菌外，革蘭氏陽性細菌化膿性鏈球菌係複雜的皮膚及皮膚結構感染(SSTI)之主要原因。本發明提供針對MRSA相關感染之潛在預防及治療。
尋常痤瘡係常見人類皮膚疾病，其特徵在於皮膚區域具有皮脂溢出、粉刺、丘疹、膿皰、結節及可能之瘢痕。受痤瘡侵襲之區域包含面部、胸上部及背部。重度痤瘡具有發炎性，但痤瘡亦可以非發炎
形式表現。細菌痤瘡丙酸桿菌可引起發炎，從而在微小粉刺或粉刺周圍之真皮中導致發炎性損傷，此導致發紅且可導致結瘢或色素過多。抗微生物短脂肽可用於呈下列形式(但不限於下列形式)之痘疤控制：筆、發泡體、擦拭巾(wipe)、乳霜、洗劑、噴霧劑、調色劑及/或清潔劑。另一潛在用途可係使用當前技術與(但不限於)水楊酸或類視色素之組合。
毛囊炎係用於闡述皮膚任一處之一或多個毛囊之任何發炎之詞語，其包含在非裔美國男性中尤其普遍之鬍鬚假性毛囊炎(例如剃刀突塊)及頭皮毛囊炎。毛囊炎係毛囊之感染。輕微情形往往導致搔癢而重度情形則可導致深度結瘢。其係因細菌經由毛囊之小開口進入皮膚所致。在毛囊炎之大多數情形下，受損毛囊隨後經葡萄球菌屬(Staphylococcus)細菌感染。須癢係面部鬍鬚區域、通常上唇處毛囊之葡萄球菌感染。須癬與須癢相似，但感染係由真菌引起。有多個建議可幫助預防此皮膚病況，例如使用抗細菌肥皂及頭皮毛囊炎洗髮精。亦已使用氫化可體松(hydrocortisone)、抗生素或維A酸(retinoin)乳霜來治療剃刀突塊引起的刺激及丘疹。本發明所闡述之廣譜抗微生物脂肽應適用於由以下引起之病症：毛囊損傷、毛囊阻塞、剃須或衣服、頭盔帶及諸如此類在頸部、腹股溝或生殖器區域引起之摩擦。
頭皮屑係常見慢性頭皮病況，其特徵在於頭皮搔癢及脫屑。馬拉色菌屬(Malassezia)係熟知酵母菌，其引起常見人類皮膚疾病，包含頭皮屑、變色糠疹、脂溢性皮炎、牛皮癬及異位性皮炎。發癬亦稱為毛髮錢癬或頭皮錢癬，其係頭皮之表面真菌感染。該疾病主要係因發癬菌屬及小芽孢菌屬(Microsporum)中之皮癬菌侵入毛幹所致。發癬菌屬感染之病例主要存在於中美洲至美國及西歐之一部分。該疾病具有感染性且可藉由人類、動物或具有真菌之物體傳播。亦存在攜帶者狀態，其中真菌存在於頭皮上但未出現臨床體徵或症狀。足癬亦稱
為足部錢癬或足癬，其亦係引起受影響區域起鱗皮、脫屑及搔癢之足部皮膚之真菌感染。其係由發癬菌引起。在一些情形下，真菌感染可伴隨有繼發性細菌感染。諸如特比萘芬(terbinafine)、伊曲康唑(itraconazole)及氟康唑(fluconazole)等抗真菌藥已開始獲得用於治療之許可。本文所揭示具有針對細菌及真菌之廣譜活性之脂二肽可具有作為局部治療用於預防所闡述病況且使其消退之潛能。
異位性皮炎(AD)係發炎性、慢性復發性、非接觸傳染性且搔癢性皮膚病症，其侵襲15%-30%兒童及2%-10%成人。異位性皮炎有時稱為濕疹或異位性濕疹，在嬰兒及兒童中最常見。其特徵在於搔癢症、濕疹性病變、乾燥症(皮膚乾燥)及苔蘚樣硬化(皮膚增厚及皮膚條紋增加)。在AD皮膚上發現之最常見細菌係金黃色葡萄球菌。實際上，大於90%之AD患者在損傷及非損傷皮膚上定殖有金黃色葡萄球菌，而5%之AD患者在健康皮膚上定殖有金黃色葡萄球菌。AD皮膚顯示表皮障壁功能缺陷以及如藉由抗微生物肽之表現降低所表明之表皮先天性免疫系統缺陷。本文所闡述具有抗微生物活性及抗發炎活性之脂肽應係AD護理之替代選擇。
口臭亦稱為呼吸臭，其係用來闡述呼吸中發散非常令人討厭之氣味之術語。口臭估計係在蛀牙及牙周病後尋求牙科幫助之第三最常見原因。呼吸臭及齒齦病係由革蘭氏陰性細菌(例如牙齦卟啉單胞菌(Porphyromonas gingivalis)、伴放線放線桿菌(Actinobacillus actinomycetemcomitans)、擬桿菌(Bacteroides spp.))引起。該等細菌亦引起口腔上皮內襯之重度發炎。具有抗發炎活性之抗革蘭氏陰性選擇性肽將適用於維持健康口腔護理。
三氯沙(Triclosan)係具有抗細菌、抗真菌及抗病毒特性之氯化芳香族化合物。其用於多種常見家居用品中，包含肥皂、漱口水、洗碗精、牙膏、除臭劑及手部消毒液。報告已提出，三氯沙可與自來水中
之氯組合形成氯仿，美國環境保護局(United States Environmental Protection Agency)將氯仿歸類為可能的人類致癌物，意指其可能引起癌症。本文所揭示之抗微生物脂二肽因具有適當抗細菌及抗真菌特性且無致癌風險而有很大可能會替代三氯沙。
類似地，體味亦受棒狀桿菌屬(Corynebacterium)之成員作用之影響。可將所闡述技術之抗微生物特性納入化妝品粉劑、凝膠、半固體、乳霜或如腋下或足部除臭劑之其他形式。
細菌性陰道炎(BV)係稱為陰道炎之陰道感染之最一般原因。通常，並不將其視為「性傳播感染」。細菌性陰道炎正侵襲20%至70%之女性。除了搔癢及灼熱感外，強烈的氣味及異常陰道分泌物係該疾病最常見之症狀。陰道念珠菌病係涉及稱為念珠菌之酵母菌或真菌之過度生長之陰道感染。此酵母菌通常如眾多其他生物體一樣存在於口、腸及陰道中。若微生物平衡遭到破壞(如在使用廣譜抗生素時、激素波動時及其他情況下可能發生)，則可發生酵母菌過度生長。陰道念珠菌病通常稱為「酵母菌感染」，其係在接近75%之成年女性之一生侵襲其之常見問題。亦與陰道發炎相關的係非白色念珠菌，例如光滑念珠菌及熱帶念珠菌；皰疹及B族鏈球菌。該等病況各異且可因乳酸桿菌(Lactobacillus spp.)之損失而惡化，乳酸桿菌係用作針對條件病原體之保護性障壁之天然共生體。因此，使用本文所揭示之抗微生物肽來控制存於(但不限於)潤滑劑中之指示微生物可提供(例如)如女性保潔產品之有效護理。
化妝品製造商將化學防腐劑添加至化妝品及洗劑以殺死細菌且延長該等產品之儲藏壽命。然而，一些防腐劑引起皮疹及其他過敏反應，且研究已將一些該等試劑與癌症及其他健康問題相關聯。在大於70%之化妝品、皮膚洗劑及除臭劑中發現諸如對羥基苯甲酸甲酯、對羥基苯甲酸丁酯及對羥基苯甲酸乙酯等合成對羥基苯甲酸酯防腐劑。
對羥基苯甲酸酯防腐劑模仿雌激素之效應。即使少量該等有效化學品亦可使身體之天然激素系統失衡。已將人工觸發的雌激素失衡與女性乳癌及年輕男孩之睪固酮缺陷相關聯。化妝品工業亦使用甲醛作為防腐劑。即使添加至化妝品之量較小，其在彼等對化學品敏感者中亦可引起過敏反應。因此，所闡述廣譜抗微生物脂二肽之一種成本有效的潛在應用係可替代有害化學品作為化妝品工業之防腐劑。
在以上治療方法中用於遞送肽之組合物可係氣溶膠、乳液、液體、洗劑、乳霜、糊劑、軟膏、粉劑或發泡體或其他醫藥上可接受之調配物。此外，該等肽可使用較少涉及之調配物(例如去離子水/蒸餾水、PBS或標準醫用鹽水溶液)來遞送。通常，醫藥上可接受之調配物將包含任何適用於人類皮膚上之載劑。該等醫藥上可接受之載劑包含乙醇、二甲基亞碸、甘油、二氧化矽、氧化鋁、澱粉及等效載劑及稀釋劑。調配物可視情況具有化妝品吸引力及/或含有諸如類視色素或其他肽等可用作本發明肽之治療作用之佐劑之其他試劑。亦可將抗生素添加至調配物以避免感染，由此允許發生最大癒合過程。組合物中肽之濃度可係約0.1 μg/mL至約50 μg/mL或約0.1 μg/mL至約10%(w/v)；然而，所採用之最終濃度可在該等範圍外變化，此端視傷口/組織病況之性質、本發明肽之生物活性及為獲得增強的組合物吸收而使用之任何佐劑或技術而定。
本發明組合物可含有一或多種發揮皮膚護理活性之其他試劑。
在本發明之較佳實施例中，倘若欲使組合物與人類角質組織接觸，則除本發明肽之外之任何其他組份應適於施加至角質組織；即，該等其他組份在納入組合物中時顯示在合理醫學判斷範圍內之過度毒性、不相容性、不穩定性、過敏反應及諸如此類。CTFA Cosmetic Ingredient Handbook，第二版(1992)闡述皮膚護理工業中常用之眾多種非限制性化妝品及醫藥成份，其適用於本發明組合物中。該等成份
類別之實例包含：磨料、吸收劑、美觀組份(例如芳香劑)、顏料、著色劑/色素、精油、皮膚感受劑(skin sensate)、收斂劑等(例如丁香油、薄荷腦、樟腦、桉樹油、丁香酚、乳酸薄荷酯、金縷梅餾出物)、抗痤瘡劑、抗結塊劑、消泡劑、抗微生物劑(例如丁基胺基甲酸碘丙基酯)、抗氧化劑、黏合劑、生物添加劑、緩衝劑、膨脹劑、螯合劑、化學添加劑、化妝品殺生物劑、變性劑、藥物收斂劑、外用鎮痛藥、成膜劑或材料、失透劑、pH調節劑、推進劑、還原劑、鉗合劑、美白及亮膚劑(例如對苯二酚、麴酸、抗壞血酸、抗壞血酸基磷酸鎂、抗壞血酸基葡糖胺)、皮膚調節劑(例如潤濕劑)、柔膚劑及/或皮膚癒合劑(例如泛醇及其衍生物、庫拉索蘆薈(aloe vera)、泛酸及其衍生物、尿囊素、甜沒藥醇(bisabolol)及甘草酸二鉀)、皮膚治療劑、增稠劑以及維生素及其衍生物。
可將本發明肽及相關組合物投與人類及動物(包含所有哺乳動物)。亦可與典型及/或實驗材料(例如組織移植物、組織培養產品、氧及敷料)組合施加。
通常，組合物可經局部、經口、經皮、全身性或藉由彼等熟習此項技術者已知可用於將本發明肽遞送至損傷部位之任何其他方法投與。組合物亦可以活體外或離體方式施加至(例如)在培養物中生長之細胞或患者移植物。
由於該等肽尺寸較小，因此預期其自身即能夠獲得一定程度的穿過皮膚之滲透率；然而，可使用某些技術來促進此移動。例如，可將親脂性(非極性)基團添加至肽或可將肽於親脂性賦形劑中遞送至皮膚，以增強肽至角質層之可及性，從而允許移位至下表皮層。以此方式，可將該等親脂性修飾視為前藥。可在賦形劑中使用諸如已知溶劑及表面活性劑等滲透促進劑以允許更好地吸收肽。預期可用於促進肽到達靶組織/損傷之專門技術包含離子電滲、電泳及超音波。離子電滲裝置係由兩個浸泡於電解質溶液中且置於皮膚上之電極組成。當跨過電極施加電流時，產生跨過角質層驅動肽遞送之電場。電穿孔涉及施加高電壓電脈衝以增加穿過脂雙層之滲透率。此在施加電流之持續時間及強度方面與離子電滲不同(離子電滲使用相對恆定的低電壓電場)。人們相信，電穿孔之高電壓電脈衝引起脂薄層膜中之親水孔之可逆形成，其可顯著增強滲透。超音波將頻率大於16 kHz之音波施加至皮膚，此導致音波所穿過之組織壓縮及膨脹。所得壓力變化產生眾
多可增強肽滲透之過程(例如空泡化、混合、溫度升高)。
以上所有肽調配物及應用皆為業內所熟知。製備及使用本發明肽之其他模式闡述於(例如)美國專利第6,492,326號及第6,974,799號中，該兩個專利之全文皆以引用方式併入本文中。
根據本揭示內容無需過多實驗即可製得且實施本文所揭示且主張之所有組合物或方法。儘管已根據較佳實施例闡述本發明之組合物及方法，但彼等熟習此項技術者將明瞭，可在不背離本發明之概念、精神及範疇下改變該等組合物及/或方法及本文所闡述方法之步驟或步驟之順序。更特定而言，應明瞭，可用某些在化學及生理上皆相關之試劑取代本文所闡述之試劑，同時可達成相同或相似結果。彼等熟習此項技術者可明瞭之所有該等相似取代及修改皆視為在本發明範疇內。
Claims (15)
- 一種式C12-18脂質-KXZ-NH2之肽，其中K係離胺酸；X係脯胺酸、d-脯胺酸、組胺酸或精胺酸；Z可視需要選用，且若存在則Z係纈胺酸、蘇胺酸、丙胺酸或白胺酸；且末端COOH經NH2醯胺化。
- 如請求項1之肽，其中該C12-18脂質係月桂酸(C12)、肉豆蔻酸(C14)、十五碳酸(C15)、棕櫚酸(C16)或硬脂酸(C18)之脂質部分。
- 如請求項1之肽，其中該肽係C12-18脂質-離胺酸-脯胺酸-纈胺酸-NH2；C12-18脂質-離胺酸-d-脯胺酸-蘇胺酸-NH2；C12-18脂質-離胺酸-脯胺酸-丙胺酸-NH2；C12-18脂質-離胺酸-脯胺酸-白胺酸-NH2；C12-18脂質-離胺酸-脯胺酸-NH2；C12-18脂質-離胺酸-d-脯胺酸-NH2；C12-18脂質-離胺酸-組胺酸-NH2；或C12-18脂質-離胺酸-精胺酸-NH2。
- 如請求項3之肽，其中該C12-18脂質係棕櫚醯基或十五碳醯基。
- 如請求項1之肽，其中該肽係棕櫚醯基-離胺酸-脯胺酸-纈胺酸-NH2；棕櫚醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；十五碳醯基-離胺酸-脯胺酸-纈胺酸-NH2；十五碳醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；硬脂醯基-離胺酸-脯胺酸-纈胺酸-NH2；硬脂醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2； 棕櫚醯基-離胺酸-脯胺酸-丙胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-白胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-NH2；棕櫚醯基-離胺酸-d-脯胺酸-NH2；棕櫚醯基-離胺酸-組胺酸-NH2；或棕櫚醯基-離胺酸-精胺酸-NH2。
- 一種組合物，其包括至少一種如請求項1之肽及醫藥上可接受之載劑。
- 如請求項6之組合物，其中該肽係以介於約0.1 μg/mL至約10%(w/v)範圍內之濃度存在。
- 如請求項6之組合物，其中該組合物係呈以下形式：氣溶膠、化妝品製劑、噴霧劑、乳液、液體、洗劑、乳霜、糊劑、軟膏、粉劑或發泡體。
- 如請求項6之組合物，其中該肽係棕櫚醯基-離胺酸-脯胺酸-纈胺酸-NH2；棕櫚醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；十五碳醯基-離胺酸-脯胺酸-纈胺酸-NH2；十五碳醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；硬脂醯基-離胺酸-脯胺酸-纈胺酸-NH2；硬脂醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-丙胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-白胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-NH2；棕櫚醯基-離胺酸-d-脯胺酸-NH2；棕櫚醯基-離胺酸-組胺酸-NH2；或棕櫚醯基-離胺酸-精胺酸-NH2。
- 如請求項6之組合物，其可用於預防或治療以下皮膚病況：痤瘡、異位性皮炎、酒渣鼻、細菌性陰道炎、頭皮屑或足癬。
- 一種如請求項6之組合物之用途，其用於製造用於預防或治療哺乳動物皮膚或黏膜組織之微生物感染之藥劑。
- 如請求項11之用途，其中該組合物包括濃度介於約0.1 μg/mL至約10%(w/v)範圍內之該肽。
- 如請求項11之用途，其中該細菌感染係由選自由以下組成之群之細菌引起：痤瘡丙酸桿菌(P.acnes)、金黃色葡萄球菌(S.aureus)、大腸桿菌(E.coli)及白色念珠菌(C.albicans)。
- 如請求項11之用途，其中該組合物之該肽係棕櫚醯基-離胺酸-脯胺酸-纈胺酸-NH2；棕櫚醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；十五碳醯基-離胺酸-脯胺酸-纈胺酸-NH2；十五碳醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；硬脂醯基-離胺酸-脯胺酸-纈胺酸-NH2；硬脂醯基-離胺酸-d-脯胺酸-蘇胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-丙胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-白胺酸-NH2；棕櫚醯基-離胺酸-脯胺酸-NH2；棕櫚醯基-離胺酸-d-脯胺酸-NH2；棕櫚醯基-離胺酸-組胺酸-NH2；或棕櫚醯基-離胺酸-精胺酸-NH2。
- 如請求項11之用途，其中該皮膚之該微生物感染係痤瘡、異位性皮炎、酒渣鼻、細菌性陰道炎、頭皮屑或足癬。
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| PCT/US2013/029696 WO2013142088A1 (en) | 2012-03-20 | 2013-03-07 | Short antimicrobial lipopeptides |
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| JP (1) | JP6261560B2 (zh) |
| KR (1) | KR20140136494A (zh) |
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| WO (1) | WO2013142088A1 (zh) |
| ZA (1) | ZA201405950B (zh) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016002767A1 (ja) * | 2014-06-30 | 2016-01-07 | ロート製薬株式会社 | 外用組成物 |
| JP6906274B2 (ja) * | 2014-06-30 | 2021-07-21 | ロート製薬株式会社 | 外用組成物、眼科用組成物、抗菌剤、及び抗菌方法 |
| WO2017035345A1 (en) * | 2015-08-26 | 2017-03-02 | The General Hospital Corporation | System and method for electrical control of bacteria |
| KR101855170B1 (ko) | 2015-11-18 | 2018-05-08 | (주)노바셀테크놀로지 | 신규 항균 펩타이드 및 그의 용도 |
| CN109320585B (zh) * | 2018-09-06 | 2021-10-26 | 南方医科大学 | 一种具有专一性抗痤疮丙酸杆菌作用及抗炎作用的短脂肽 |
| US20220257569A1 (en) * | 2018-09-12 | 2022-08-18 | The Governing Council Of The University Of Toronto | Indole-oxadiazole compounds and their therapeutic use |
| CN111035764B (zh) * | 2018-10-14 | 2021-09-07 | 深圳市健元医药科技有限公司 | 一种治疗类风湿性关节炎的组合物及其制备方法 |
| CN110279844A (zh) * | 2019-01-31 | 2019-09-27 | 浙江星杭泰乐生物医药有限公司 | 人工合成抗菌肽在制备抑菌消炎祛痘化妆品或外用药物制剂中的应用及抑菌消炎祛痘组合物 |
| CN111303242B (zh) * | 2020-02-27 | 2022-04-26 | 广州领晟医疗科技有限公司 | 一种KdPT的修饰肽 |
| KR102163568B1 (ko) * | 2020-08-21 | 2020-10-07 | 주식회사 비드테크 | 지방산 항균펩타이드 및 이를 함유하는 항균 조성물 |
| CN116348087B (zh) * | 2020-09-29 | 2025-03-28 | 联合利华知识产权控股有限公司 | 包含氨基酸的个人护理组合物 |
| US11793746B2 (en) * | 2020-10-01 | 2023-10-24 | Chanda Zaveri | Intense skin hydration systems and methods |
| CN112679576B (zh) * | 2020-11-06 | 2022-09-20 | 黄石瀚海新材料科技有限公司 | 抗菌脂肽、抗菌脂肽水凝胶制备方法及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993008815A1 (en) * | 1991-10-28 | 1993-05-13 | Cytoven | Pharmaceutical dipeptide compositions and methods of use thereof |
| JP3273314B2 (ja) * | 1998-08-12 | 2002-04-08 | 独立行政法人農業生物資源研究所 | 抗菌ペプチド及びこれを有効成分とする抗菌剤 |
| US6492326B1 (en) | 1999-04-19 | 2002-12-10 | The Procter & Gamble Company | Skin care compositions containing combination of skin care actives |
| DE10106852A1 (de) | 2001-02-14 | 2002-09-05 | T Luger | Entzündungshemmende Verbindungen |
| SE0300207D0 (sv) * | 2003-01-29 | 2003-01-29 | Karolinska Innovations Ab | New use and composition |
| WO2004110341A2 (en) * | 2003-06-19 | 2004-12-23 | Yeda Research & Development Co. Ltd. | Antimicrobial and anticancer lipopeptides |
| JP4256389B2 (ja) | 2003-11-17 | 2009-04-22 | セダーマ | テトラペプチドとトリペプチドの混合物を含む組成物 |
| FR2870244B1 (fr) * | 2004-05-11 | 2011-01-07 | Centre Nat Rech Scient | Conjugues dipeptidiques antagonistes de l'alpha-msh |
| DE102004055541A1 (de) * | 2004-11-17 | 2006-05-18 | Henkel Kgaa | Kosmetische und dermatologische Zusammensetzungen zur Behandlung reifer Haut |
| US20100215726A1 (en) * | 2009-02-25 | 2010-08-26 | Peter Thomas Roth | Compositions for Diminishing the Appearance of Wrinkles |
| CN102329375A (zh) * | 2011-09-30 | 2012-01-25 | 中国药科大学 | 一组末端酰胺化的抗菌肽 |
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Also Published As
| Publication number | Publication date |
|---|---|
| RU2627648C2 (ru) | 2017-08-09 |
| KR20140136494A (ko) | 2014-11-28 |
| RU2014142038A (ru) | 2016-05-10 |
| ES2729237T3 (es) | 2019-10-31 |
| US20150080291A1 (en) | 2015-03-19 |
| EP2827907B1 (en) | 2019-03-06 |
| AR090439A1 (es) | 2014-11-12 |
| CN104379177B (zh) | 2017-07-04 |
| ZA201405950B (en) | 2017-08-30 |
| AU2013235692A1 (en) | 2014-09-25 |
| MX2014011290A (es) | 2014-10-13 |
| EP2827907A1 (en) | 2015-01-28 |
| RU2017127273A (ru) | 2019-02-04 |
| CN104379177A (zh) | 2015-02-25 |
| WO2013142088A1 (en) | 2013-09-26 |
| JP6261560B2 (ja) | 2018-01-17 |
| CA2864179A1 (en) | 2013-09-26 |
| DK2827907T3 (da) | 2019-06-11 |
| US9278994B2 (en) | 2016-03-08 |
| JP2015512386A (ja) | 2015-04-27 |
| CN107080831A (zh) | 2017-08-22 |
| AU2013235692B2 (en) | 2016-12-08 |
| SG10201607784VA (en) | 2016-11-29 |
| TWI541254B (zh) | 2016-07-11 |
| PL2827907T3 (pl) | 2019-08-30 |
| MY163100A (en) | 2017-08-04 |
| HK1204453A1 (zh) | 2015-11-20 |
| SG11201405244RA (en) | 2014-10-30 |
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