CN110650970B - 抗菌肽及其药品 - Google Patents
抗菌肽及其药品 Download PDFInfo
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- CN110650970B CN110650970B CN201880003993.4A CN201880003993A CN110650970B CN 110650970 B CN110650970 B CN 110650970B CN 201880003993 A CN201880003993 A CN 201880003993A CN 110650970 B CN110650970 B CN 110650970B
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Abstract
本发明提供一种抗菌肽及其药品,涉及医学领域。本发明的抗菌肽通式:Y‑Ile‑Leu‑Pro‑X‑Lys‑X‑Pro‑X‑X‑Pro‑X‑Аrg‑Arg‑NH2,其中Х=4‑硝基苯基丙氨酸;4‑氯苯丙氨酸;4‑甲氧基苯丙氨酸;D‑苯丙氨酸;4‑氨基苯丙氨酸;4‑氨基苯甲酰基苯丙氨酸;高苯丙氨酸;4‑叔丁基丙氨酸苯;2‑甲基苯丙氨酸;4‑氟苯丙氨酸;五氟苯丙氨酸或2‑三氟甲基苯丙氨酸;Y=H或棕榈酰或有抗菌活性的2ˊ‑亚胺基二乙醇.本发明还提供含有肽的活性成分具有抗菌性能的凝胶,其特征在于它含有本权利要求2、3或4的合成肽及辅料。浓度为0.001‑0.1质量%。本发明的肽针对细菌、霉菌,孢子和病毒具有杀菌特性。用本发明的肽制备的凝胶可用于治疗细菌性、病毒性及综合感染性疾病。
Description
技术领域
本发明涉及医学领域,即具有杀菌作用的新肽,特别是具有抗菌,抗真菌及抗病毒属性的新肽及在此基础上开发的药物。
背景技术
目前,传染疾病的病原体对抗菌药物的抗药性有升高的趋势,这降低了治疗社会性重大传染疾病的有效性。此外,一个重要的致病因素是细菌和病毒的混合感染。在这方面,迫切的任务是寻找新的治疗方法。众所周知,在保护高等真核生物抵御感染过程中机体包括天然肽内源性化合物的分泌,它们是以活性保护成分的形式处理以前基因信息而生成的,其特点是比抗体,特异性吞噬细胞的形成,速度更快,消耗能源更少。[Mangoni,M.L.Host-defense peptides:frombiology to therapeutic strategies//Cell.Mol.Life Sci.-2011.-68.-р.2157–2159].以这种内源性多肽化合物为基础的药物的开发是解决微生物对现有抗生素耐受性问题的可能途径之一。目前,这类药物已经在医院使用或在进行临床试验。[Brogden,N.K.,and Brogden,K.A.Will new generationsofmodified antimicrobial peptides improve their potential aspharmaceuticals?//Int.J.Antimicrob.Agents.-2011.-38.-р.217–225.Yeung,A.T.Y.,Gellatly,S.L.,and Hancock,R.E.W.Multifunctional cationic host defensepeptides and their clinical applications//Cell.Mol.Life Sci..-2011.-68.-р.2161–2176].公开资料显示,[RU 2183643,2002]专利作者创建的肽的普通公式为H-a-Lys-b-Trp-Lys-c-Pro-d-Lys-Pro-Trp-e-Arg-NH2,这里а=-Ile-或-Lys-;b=-Pro-或-Lys-;с,d=-Lys-或-Trp-;е=-Arg-或-Ala.这些肽的缺点是对真菌和病毒的活性不够高。与上述肽结构最近似的是肽Indolicidin[Selsted M.E.,Novotny M.J.,et al/,Indolicidin,a novel bactericidal tridecapeptide amide from neurophils.//J.Biol.Chemistry.-vol.267.-№7.-1992.-p.4292-4295],它的结构式:H-Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Аrg-Arg-NH2.该肽对多种细菌具有抗菌活性,但对病毒感染无效。Indolicidin的另一个缺点是较高的溶血活性的存在。目前已知,有多种在具有杀菌作用的肽的基础上开发的外用药。例如,《活力肽》[http://tiu.ru/Gel-dlya-litsa-s-peptidami.html?no_redirect=1];《肌体新生》系列[http://lifehappiness.narod.ru/screens/cosmetics/gels.htm];红素衍生物与氨基酸和肽[RU2415868,2011].
上述所有药剂都是由肽的活性成分和辅助成分组成。这些药物的缺点是相对较低的杀菌活性,使用肽混合物,纯天然来源,但往往没有具体成分。最贴近该申报药物的是一种凝胶allomedin,含有作为活性成分的肽allostatin,以及辅助物质-卡波姆、水、尿囊素、苯基乙二醇单醚、乙基己基甘油、氢氧化钠[www.stada.ru/press/.../allomedin-preparat-novogopokoleniya-protiv-gerpesa-0.html;http://www.biomedservice.ru/price/goods/62/2582].凝胶缺点是可以使用的区域有限(只能适用于病毒感染的皮肤)。
发明内容
本发明的目的是开发对各种微生物群都能给予有效影响的肽,以及在其基础上开发的外用剂型。结果发现,上述问题是通过合成Indolicidin新的类似物的方式得以解决,它们的特点是由苯丙氨酸衍生物氨基酸残基组成,苯丙氨酸衍生物包含在芳香环上的电子供体和电子受体取代基。
本发明提供一种抗菌肽,具有通式:Y-Ile-Leu-Pro-X-Lys-X-Pro-X-X-Pro-X-Аrg-Arg-NH2,
其中Х=4-硝基苯丙氨酸(Phe(NO2));4-氯苯丙氨酸(Phe(Cl));4-甲氧基苯丙氨酸(Phe(OCH3));D-苯丙氨酸(-D-Phe);4-氨基苯丙氨酸((4-NH2)Phe);4-氨基苯甲酰基苯丙氨酸((4-NHBz)Phe);高苯丙氨酸(homoPhe);4-叔丁基苯丙氨酸((4-But)Phe);2-甲基苯丙氨酸((2-Me)Phe);4-氟苯丙氨酸((4-F)Phe);五氟苯丙氨酸(Phe(F5));或2-三氟甲基苯丙氨酸((2-CF3)Phe);Y=H或棕榈酰(Pal)或氨基十一酰(H2N-(CH2)10-CO)。
利用标准肽合成工艺固相萃取获得多肽[J.M.Steward and J.D.Young,"SolidPhase Peptide Synthesis",W.H.Freeman Co.,San Francisco,1969]保护基团随后裂解,利用高效液相色谱法进行最终产物的纯化(ВЭЖХ)。
作为氨基酸α-氨基组间隔保护采用固相合成法时使用叔丁氧羰基组。三甲苯磺酰或硝基组隔断瓜诺精氨酸组,赖氨酸∈--氨基组隔断2-氯苯甲腈保护。借助1-羟基苯并三唑酯实现肽链增长。使用茚三酮试验或溴酚蓝(脯氨酸)监测反应的完备性。在清除剂存在条件下,用氟化氢从树脂中裂解肽并去除保护基团。借助于反相高效液相色谱法纯化合成肽。所得制剂纯度达98%以上。它们都有满意的氨基酸分析和正确的质谱数据。合成肽的结构见表1。
表1-合成的肽类似物的主要结构
试验表明,新研发的肽把抗菌活性,对真菌和酵母菌及病毒的杀菌活性结为一体。与壳内多个微孔形成相关的肽灭活细菌的可能机制,这些微孔导致渗透压的调整,内容的流动和类核毁灭。
最好的效果是使用肽2,6和11,其结构如下所示:
(2)NH2-(CH2)10-CO-Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH2;
(6)H-Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH2;
(11)H-Ile-Leu-Pro-(2-Me)Phe-Lys-(2-Me)Phe-Pro-(2-Me)Phe-(2-Me)Phe-Pro-(2-Me)Phe-Arg-Arg-NH2.
可见,较高抗菌活性,主要表现在剂量1-5微克/毫升范围内,合成肽在剂量大于200微克/毫升时也不会引起溶血。此外,这些肽对免疫细胞有影响。因此,在2-10μg/mL的剂量范围他们明显增加胸腺细胞自发增殖和减少脾脏细胞掺入3H-胸腺嘧啶。在脂多糖(LPS)刺激脾细胞增殖时,在剂量0.4-2μ克/毫升的肽抑制LPS。在剂量为0.4–10μ克/mL时肽用脂多糖刺激的巨噬细胞系RAW264.7抑制产品NO。肽与脂多糖结合的特异性也证实了抑制产品NO的效率随脂多糖刺激剂量的减少而增加。
工业适用性
在研发上述多肽的基础上,发现一种具有杀菌活性的外用药剂。本品为透明均匀的凝胶,外用,无杂质。凝胶具有以下成分(质量%):活性成分(肽)-0,001-0,1;辅料-99,999-99,9.作为活性成分,使用上述的肽2,6或11。作为辅助添加剂可用溶剂如水或醇水溶液、香料、抗氧化剂,及其它有助于优化肽的杀菌药物性取向的其他物质。特别是,作为凝胶辅助添加剂包括卡波姆、尿囊素、苯氧乙醇、乙烯己基甘油、氢氧化钠、透明质酸钠、薰衣草或蓖麻油、甘油、羧甲基纤维素钠、柠檬酸、α-生育酚乙酸酯、苯甲酸等。
研发这个制剂完全是按照生产软剂型技术标准进行的,作为活性成分使用了药学上适宜的肽盐,不会产生有害的局部和全身副作用,作为辅料,使用了适当的添加剂,它们提供结构粘度,具有假塑性,塑性和触变性特性,能提高活性成分的生物利用度。
具体实施方式
通过以下示例说明本发明的实际适用性。
实施例1.合成肽1及3-14
表2-氨基酸残基的附着程序
如果茚三酮试验呈阳性,从步骤3开始,重复凝结。
在肽基树脂合成完成后,在反应容器中用5毫升50%三氟乙酸加入在二氯甲烷中处理,用5毫升二氯甲烷洗涤,过滤,从容器中移到过滤漏斗。每次用5毫升异丙醇过滤冲洗三次,每次用无水乙醚5毫升冲洗三次。在真空干燥器在五氧化二磷上干燥得到的肽基树脂,0.2克产品最终解封的程序如表3所示。
表3-肽基解封及肽与聚合物基体裂解程序
得到的粗品进行反相高效液相色谱C18柱Nova Pack纯化,19х300мм,300A0,梯度0-70%乙腈,0.1%三氟乙酸。基本物质含量-肽序列1,3-14,根据光密度不小于98%。肽的氨基酸组成及其分子质量与理论相符。
实施例2.合成肽2和15
作为保护精氨酸的功能使用三甲苯磺酰基组。为合成肽向反应釜中加入10毫升二甲基甲酰胺,再加入0.2克N-丁基羟基羰基-/>-三甲苯磺酰-精氨酰-甲基二苯氨基聚合物。肽链按程序从C端增长,如表2所示,在最后阶段添加棕榈酸(15)或boc-11-氨基癸酸(2)。
由此所获肽基树脂用无水氟化氢处理,并按表3所示的程序析出粗品。使用高效液相纯化时乙腈梯度12-90%加入0.1%三氟乙酸。
实施例3.合成肽对细菌的杀菌活性。
使用琼脂糖凝胶径向扩散法测定其抗菌活性。在进行实验时,约4х106菌落形成单位(CFU)在平均对数生长期阶段,分散在10毫升的凝胶层上(10mm磷酸钠,0.3毫克大豆培养基水解粉和1毫升1%(重量/体积)琼脂糖)。准备系列稀释的肽在含0.1%人血清白蛋白的0.01%乙酸中。8μL肽样品涂到凝胶层上。涂肽3个小时后再涂上上层(10毫升水解大豆琼脂,60克/L)。经过一个晚上的孵化,测量透明区,准确度为0.1毫米。肽的活性表示在相对单位为1毫米=10U。系列稀释肽样品区域直径的回归线x轴上的段值被确定为MIC。所有测量均以三线进行。
试验结果证明,当作用于细菌,包括耐抗生素细菌时,所有的肽都具有很高的生物活性,在某些情况下,超过肽1(indolizidine)的效力。最好的结果是使用肽2,6和11时达到的。
实施例4.对真菌和酵母菌的杀菌活性
用类似于实施例3的方法对Candida albicans 820菌株进行抗真菌活性评价。
结果表明,在剂量3-10毫克/毫升时,肽2,4,6,8,11和13对真菌和酵母菌表现出的杀菌活性,显著高于indolizidine的活性。
实施例5.肽的溶血活性。
在确定溶血活性时由肝磷脂处理的血离心分离出红细胞经巴比妥缓冲液洗三次(0.15M,pH 7.4)。然后将混合物稀释用磷酸盐(PBS)缓冲液(0015M磷酸氢二钠,0.15MNaCl,pH 7.4)。将肽样品放到磷酸盐(PBS)缓冲液中,再置于96孔板的小孔里,向PBS加入红细胞悬液。红细胞浓度为1%。作为阴性对照(无溶血)使用了PBS。作为阳性对照(100%红血球溶解)在PBS里加入了0.1%Triton X-100。血红蛋白释放率
将96孔板在37℃在5%CO2大气中孵化3个小时并离心。上清液被移到干净的小片上。被破坏的红细胞血红蛋白的释放率的测定采用分光光度计“victor-2”(芬兰)在λ=450nm条件下。MIH 50被定义为最低浓度,这样的情况下有50%溶血。所有测量均以三条线进行。
肽2,6,11在1-5μμg/ml剂量范围内有较高的抗菌活性,在剂量大于200微克/毫升,也不能引起溶血。
实施例6.所获肽的抗病毒活性
为评估肽的抗菌作用,试验中采用以下菌株:流感病毒H3N2(VG,APERT/16);腺病毒3型(AB 3株/沃罗涅日/2174/82);副流感病毒3型(ВП3,bok)。从俄罗斯科学院流感病毒研究所得到的流感病毒;副流感病毒,腺病毒是从俄罗斯国家病毒收藏品展览室获取的。试验中,我们使用了细胞移植培养的人的喉癌Hep-2细胞和MDCK犬肾细胞。
每种药剂1mg溶于2mL DMSO,加入到一个营养培养基瓶(2NEEDLE MEM and 199,taken in equalproportions)至最终浓度为20μ克/毫升;2000μμg/ml,0.2áμg/ml和0.02μ克/毫升。在有效面积为25平方厘米的培养床上获得单层细胞培养物。在感染前除去生长介质,单层细胞用Hanks溶剂洗涤一次。移植细胞培养物Нeр-2被腺病毒或副流感病毒3型感染;MDCK细胞培养物被流感病毒感染,为保证感染的多样性使用多个0.1和0.01TCID50株感染细胞。
与感染试验平行进行的是,在实验中使用相同的培养床与未感染细胞培养物Hep-2和MDCK细胞,其中一部分是作为对照细胞,一部分用于确定药物对细胞的毒性作用。
向感染试验培养床加入不含本专利肽的培养液(PS),对照病毒,及含本专利肽2、6、11的培养液,它们在2000μμg/ml,0.2áμg/ml和0.02μ克/毫升剂量时,都表现出较高的对细菌和真菌的杀菌活性。同样成分的PS也被加入到未感染的细胞培养床(对照药物)中。向另一部分未感染的细胞培养物添加不含肽的PS(对照细胞)。
观察3到4天,取决于对照床上病毒的致细胞病变作用的发展情况(对照病毒)。对加入不含本专利肽的培养液(PS),及含本专利肽的培养液的未受感染细胞培养物,每天用显微镜对药物对细胞的毒性作用进行评估。在观察期结束时含有培养液的病毒样本(SCW)进行滴定,测定实验和对照样品的感染活性。
为此,在种植浓度中备好的各0.1毫升Hep-2和MDCK细胞悬液,放在聚苯乙烯细菌生长板的孔中。经过24-48小时形成单层,向细胞加入稀释的病毒培养液,从1:10到1:1000000,生长培养基的10倍比率,随后每0.1毫升稀释液放置到4个细菌生长板的孔中。六个孔作为对照细胞,加入0.1毫升培养基。感染的和对照细胞在培养箱中用5%的二氧化碳在34,5±0,5℃С的温度下固定放置。统计滴定的结果要进行3天(流感病毒)或4天(副流感病毒,腺病毒),看病毒是否有直接致细胞病变作用(TSPD)。病毒繁殖的活性按Reed,Muench方法计算受感染滴度的大小进行评估。
结果表明,在20μ克/毫升或2μ克/毫升时,测试的肽导致流感病毒H3N2(VG,APERT/16株)、腺病毒3型(AB,3株/沃罗涅日/2174/82)、副流感病毒3型(ВП3,strain the Wok)明显的(超过100-1000倍)感染活性降低。使用肽的剂量为0.2μ克/毫升时,在较小程度上,但明显(超过10-100倍)降低流感病毒和腺病毒的感染活性。
实施例7.肽对免疫细胞的影响
研究肽对小鼠胸腺和脾脏细胞自发和有丝分裂原刺激增殖的影响。小鼠胸腺取自无菌条件下,均值化处理,在培养基RPMI-1640(Sigma)中悬浮,两层纱布过滤。取出的悬浮细胞在RPMI-1640培养基洗2次,再使其悬浮在含2毫米谷氨酰胺(Sigma)和80μ克/毫升庆大霉素的培养基中。细胞数量用血细胞计数器计算。用含4%胎儿血清的培养基(FCS)(Sigma)调整细胞浓度到10х106/毫升。
小鼠脾脏取自无菌条件下,在培养基RPMI-1640均值化处理,两层纱布过滤。所获匀浆离心处理,然后分解红细胞,使用0.83%氯化铵溶液。用RPMI-1640培养基洗2次脾细胞。细胞数量用血细胞计数器计算。脾细胞浓度在RPMI-1640培养基中增加2mm谷氨酰胺,80μμg/ml庆大霉素和20%FCS调整为每毫升5х106。为刺激胸腺和脾细胞的增殖使用脂多糖(Sigma)在最终浓度为0.2和0.02μ克/毫升。在体外试验研究合成的indolizidine类似物对淋巴细胞增殖形成的影响时,研究是在使用不同浓度的药物的情况下进行的(浓度范围从10到0.016μ克/毫升)。试验时使用平底96孔培养板(Costar)。细胞培养时温度37℃,大气中含有5%的CO2,时间为72小时。在培育进行到56个小时时向培养板的所有小孔中倒入浓度为5μCI/ml的3H-胸腺嘧啶核苷(同位素)。在培育结束时,细胞培养物通过收集器转移到过滤器,干燥过滤物,用液体闪烁计数器(rackbeta 1217)测算得到的包括3H-胸腺嘧啶核苷的细胞培养物数量。结果以每分钟脉冲数表示。具体数据见表4-7。
表4-肽对胸腺自发性细胞增殖的影响
*р<0.05**р<0.01
表5-肽对脾细胞自发增殖的影响
*р<0.05**р<0.01
表6-肽对LPS激励(0.02微克/毫升)的小鼠脾细胞增殖的影响
*р<0.05**р<0.01
表7-肽对LPS激励(0.2微克/毫升)的小鼠脾细胞增殖的影响
*р<0.05**р<0.01
在CO2孵化箱中,RAW 264.7系巨噬细胞在48孔培养板小孔中培养16个小时,培养液浓度1х106/毫升,每孔0.5毫升,含DMEM培养基/F-12(Sigma)添加2mmL-谷氨酰胺,80μ克/毫升庆大霉素和10%FCS。在孵化结束时,所有培养板小孔中的培养液被0.25毫升的新鲜培养液替换。在CO2孵化箱中,所研药剂在40、8和1.6μμg/ml浓度中与脂多糖(0.8和0.16μ克/毫升)孵化两小时。作为抑制脂多糖作用的阳性对照,在相同的浓度条件下,使用了多粘菌素B(Calbiochem)(PMB)。然后将配制好的混合物添加到培养板小孔中,不少于2排。对照组小孔中,添加脂多糖与培养液混合液。在CO2孵化箱中,培养细胞一昼夜。依生产商的说明书使用商业试剂(Sigma)用重氮化反应方法按培养液中亚硝酸盐的总水平测定productionNO。测试结果见表8-9。
表8-肽与0.2μg/mL脂多糖激励RAW264.7系巨噬细胞的方式对production NO的影响(抑制productionNO%)
表9-肽与0,04μg/mL脂多糖激励RAW 264.7系巨噬细胞的方式对production NO的影响(抑制productionNO%)
可见,肽2,6,11对免疫细胞有影响。因此,在2-10μg/mL的剂量范围他们明显增加胸腺细胞自发增殖和减少脾脏细胞掺入3H-胸腺嘧啶。在脂多糖(LPS)刺激脾细胞增殖时,在0.4-2μ克/毫升剂量范围内的肽抑制LPS。此外,在10–0.4ág/mL剂量范围内肽用RAW264.7系巨噬细胞抑制脂多糖激励的productionNO。肽与脂多糖结合的特异性也证实了抑制productionNO的效率随脂多糖刺激剂量的减少而增加。
实施例8.制备预防和治疗皮肤和粘膜疾病用凝胶
用带搅拌器的化学反应器制备凝胶。按配方向反应器加入以下成分(质量%):聚羧乙烯(1,5-2,0%)、蒸馏水、NaOH溶剂(1,5-2,0%),搅拌,放置30分钟。然后用柠檬酸调至pH 6,分次搅拌,注入含防腐剂的肽水溶液,作为防腐剂使用了0.01-0.2质量%的对羟基苯甲酸甲酯和0.002-0.01质量%的对羟基苯甲酸丙酯。由此产生的混合物再被加入1.5-2.5%质量的甘油。上述混合物搅拌10分钟,测取ph值。然后放置一昼夜使其熟化。接着将凝胶重新混合,所得的均匀凝胶被包装在容器(管)中。结果是,获得一个外用,局部用,无外来粒子的均匀的透明凝胶。局部(局部)管理,没有外来粒子。凝胶组分(%质量)如下:肽–0001-0,1;辅料-99999-99,9。含肽凝胶制剂的特性见表10。
表10.含肽凝胶制品的组分
实施例9.基于多肽的抗单纯疱疹病毒2型药剂的抗病毒活性的体内实验实验分12组,每组15只小鼠:
1-10组-感染单纯疱疹病毒2型用多肽药物凝胶(实验组);11组-感染单纯疱疹病毒2型使用阿昔洛韦(对照药);
12组-感染单纯疱疹病毒2型未使用药物(对照病毒)。
疱疹病毒感染试验。
在研究中我们使用了2型单纯疱疹病毒G菌株(ATCC vr-734,美国)。病毒先在T-98G(人脑胶质母细胞瘤)细胞培养基中孵化,后用于不同组小鼠,主要是经过小鼠的顺序脑内通道进行试验。为制备最终的感染物质,用二通道脑组织匀浆感染小鼠颅内,在感染后第四天,处死小鼠,取出脑组织,制备匀浆,并用其感染Vero细胞,在37℃和5%℃O2条件下孵育48小时。把预先确定的病毒的感染性滴度滴到培养液中,作为感染材料。作为比较药物使用了Zovirax(羟乙氧鸟嘌呤5%软膏)。对小鼠阴道上皮的损伤是用阴道涂片划痕器进行的,然后1-11组小鼠被用剂量为106TCID50体积30μL感染材料感染。在小鼠伤口上涂抹药物按试验计划进行:感染后1,2,3、4、5天,每天一次。对小鼠进行为期18天的观察。各组中缺乏带疱疹性阴道炎(白带)及其并发症(后肢麻痹)症状的小鼠,可以作为判断死亡结束的依据。是通过与疱疹性阴道炎症状组中的小鼠缺乏判断(白带)及其并发症(的后肢麻痹)。每日记录对照组和实验组小鼠的死亡率。已收到的各组小鼠死亡率为基础,计算死亡率百分比(对照时死亡小鼠数量与组内小鼠感染总数的关系),保护指数(对照组和实验组死亡率差别与对照组死亡率的比率)和每天试验中小鼠的平均预期寿命(SPM)。肽的保护活性是通过与未接受治疗的对照组相比,降低特异性死亡率和增加小鼠的寿命来评估的。肽的保护活性数据见表11。
表11-药剂在治疗单纯疱疹病毒2型引起的小鼠阴道致命的疱疹病毒感染(n=15)时的保护性活性。
数据证明,使用2c和2б药剂的效果最好。研究表明,本发明的肽针对细菌、霉菌,孢子和病毒具有杀菌特性。最好的结果是在使用肽2,6,11时获得的。肽基凝胶可用于治疗细菌性、病毒性及综合感染性疾病。
SEQUENCE LISTING
<110> 长春艾迪尔医用科技发展有限公司
<120> 抗菌肽及其药品
<140> CN201880003993.4
<141> 2018-01-29
<150> RU2017103887
<151> 2017-02-06
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> synthesized
<400> 1
Ile Leu Pro Trp Lys Trp Pro Trp Trp Pro Trp Arg Arg
1 5 10
Claims (5)
1.抗菌肽,其特征在于,通式如下:
Y-Ile-Leu-Pro-X-Lys-X-Pro-X-X-Pro-X-Arg-Arg-NH2,
其中X=4-硝基苯丙氨酸,或D-苯丙氨酸,或2-甲基苯丙氨酸,或4-氟苯丙氨酸;Y=H或H2N-(CH2)10-CO。
2.根据权利要求1所述的抗菌肽,其特征在于,结构式如下:H-Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH2。
3.根据权利要求1所述的抗菌肽,其特征在于,结构式如下:H-Ile-Leu-Pro-(2-Me)Phe-Lys-(2-Me)Phe-Pro-(2-Me)Phe-(2-Me)Phe-Pro-(2-Me)Phe-Arg-Arg-NH2。
4.根据权利要求1所述的抗菌肽,其特征在于,结构式如下:H2N-(CH2)10-CO-Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH2。
5.一种具有抗菌性能的凝胶制剂,其特征在于,其含有权利要求1-4中任一项所述的抗菌肽及辅料,所述抗菌肽按照0.001-0.1wt.%的浓度。
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RU2017103887A RU2678985C2 (ru) | 2017-02-06 | 2017-02-06 | Биоцидный пептид и препарат на его основе |
RU2017103887 | 2017-02-06 | ||
PCT/RU2018/000037 WO2018143840A1 (ru) | 2017-02-06 | 2018-01-29 | Биоцидный пептид и препарат на его основе |
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CN110650970A CN110650970A (zh) | 2020-01-03 |
CN110650970B true CN110650970B (zh) | 2023-06-02 |
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EP (1) | EP3578566B1 (zh) |
CN (1) | CN110650970B (zh) |
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US11174288B2 (en) | 2016-12-06 | 2021-11-16 | Northeastern University | Heparin-binding cationic peptide self-assembling peptide amphiphiles useful against drug-resistant bacteria |
RU2673807C2 (ru) * | 2017-05-05 | 2018-11-30 | Общество с ограниченной ответственностью "Научно-производственная фирма "ВЕРТА" | Средство, обладающее биоцидным действием |
RU2730021C1 (ru) * | 2019-10-08 | 2020-08-14 | Общество с ограниченной ответственностью "Научно-производственная фирма ВЕРТА" | Средство местного применения для лечения инфекционных вагинитов |
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US6303575B1 (en) * | 1998-05-12 | 2001-10-16 | The Regents Of The University Of California | Indolicidin analogs and methods of using same |
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- 2018-01-29 EP EP18747340.0A patent/EP3578566B1/en active Active
- 2018-01-29 WO PCT/RU2018/000037 patent/WO2018143840A1/ru unknown
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Also Published As
Publication number | Publication date |
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RU2678985C2 (ru) | 2019-02-05 |
WO2018143840A1 (ru) | 2018-08-09 |
CN110650970A (zh) | 2020-01-03 |
US11059860B2 (en) | 2021-07-13 |
RU2017103887A3 (zh) | 2018-12-17 |
US20200071358A1 (en) | 2020-03-05 |
RU2017103887A (ru) | 2018-08-06 |
EP3578566A4 (en) | 2020-02-19 |
EP3578566C0 (en) | 2023-07-19 |
EP3578566A1 (en) | 2019-12-11 |
EP3578566B1 (en) | 2023-07-19 |
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