CN1193747C - 具抗hiv活性的联苯酮醛衍生物 - Google Patents
具抗hiv活性的联苯酮醛衍生物 Download PDFInfo
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- CN1193747C CN1193747C CNB018069568A CN01806956A CN1193747C CN 1193747 C CN1193747 C CN 1193747C CN B018069568 A CNB018069568 A CN B018069568A CN 01806956 A CN01806956 A CN 01806956A CN 1193747 C CN1193747 C CN 1193747C
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Abstract
xenaldial、xenalemine和xenalic acid在治疗HIV感染和相关疾病,尤其是AIDS中的用途。本发明还涉及组合制剂形式的药物组合物,其包含选自xenaldial、xenalamine和xenalic acid的化合物以及至少一种选自蛋白酶抑制剂、逆转录酶抑制剂和整合酶抑制剂的抗HIV药剂。
Description
本发明涉及病毒感染的治疗。更具体地,本发明涉及因其抗流感病毒的抗病毒活性而众所周知的分子在治疗由人类免疫缺陷性病毒(HIV)所致感染上的用途。
逆转录病毒HIV是一种综合征疾病的致病原,该综合征疾病导致免疫系统的进行性破坏(获得性免疫缺陷综合征(acquired immune deficiencysyndrome);AIDS)以及中枢和周围神经系统的退化。
逆转录病毒在病毒复制周期的两个方面与其它病毒不同:1)通过病毒RNA基因组逆转录,导致双链cDNA拷贝的生成,以及2)cDNA整合至宿主DNA。整合是一个多阶段过程,其包括:整合酶与特定病毒DNA序列之间进行的稳定复合体的装配、随后的细胞核内裂解加工过程(以从病毒DNA的每一3’端移去末端二核苷酸)以及链转移(在此过程中病毒DNA 3’端共价连接至细胞DNA)。为了开发用于治疗HIV感染的新化合物,目前对整合机制进行了广泛研究(1-6)。特别令人感兴趣的是发现在细胞培养物中整合酶抑制剂在抗HIV上有效。在这方面,Hazuda报道了新整合酶抑制剂的鉴定,这些整合酶抑制剂的抗病毒活性直接与它们对整合的作用相关(7)。
联苯酮醛衍生物是一组因其具有抗病毒活性而众所周知的分子(8)。特别是,已证实化合物xenalamine(对-(α-乙氧基-对-苯基苯乙酰-氨基)苯甲酸)和xenaldial(二水合4-4’-双-联苯乙二醛)具抗A-PR8流感病毒(9)、MHV-3肝炎病毒及多种虫媒病毒(Arbovirus)、痘病毒(Poxvirus)、尼他病毒(Nitavirus)和粘液病毒(Myxovirus)株的活性。
本发明人对具有病毒整合酶抑制活性的新化合物进行了广泛的研究,并且他们发现一些联苯酮醛衍生物能够减少且在某些情况下甚至抑制HIV病毒在培养的感染细胞中的生长。在多种测试化合物中,xenalamine、xenaldial和xenalic acid显示出显著的杀病毒活性,并在较低程度上显示对病毒体外复制的抑制活性。化合物xenaldial被证实尤其有效。
因此,第一方面,本发明涉及xenalamine、xenalic acid以及优选的xenaldial的用途,用于制备治疗HIV感染的药物。
在用于测定化合物活性的体外培养物中,xenaldial能显著减少细胞内及细胞外的病毒含量。更精确地,观察到与对照相比,由细胞释放的病毒延迟24小时出现在液体中,且直至感染后72小时,细胞内病毒量与对照相比减少了一个对数单位以上。随后,由于化合物的逐渐失活,认为培养液中的病毒含量与对照中的含量相当。然而还观察到感染48小时后再次施用xenaldial,直至120小时仍能显著减少细胞内和细胞外的病毒量。
总的看来,实验结果证实xenaldial能发挥抗HIV病毒的杀病毒作用以及对所述病毒繁殖机制的抑制活性。更具体地,xenaldial被证实干扰病毒生物学周期的细胞内阶段。尽管其分子机制还未完全阐明,这种药物对HIV生长的抑制作用可能是由于其对整合酶的抑制活性。无论如何,公开于此的具抗HIV活性的化合物的作用机制不限制本发明。
至于xenalic acid和xenalamine,发现它们对细胞外病毒颗粒发挥显著的杀病毒活性,然而在相同实验条件下,它们对细胞内病毒复制的抑制作用低于xenaldial。
因此,xenaldial、xenalamine和xenalic acid可以用于HIV感染及相关疾病的治疗,尤其是AIDS。此外,它们可用于治疗HIV感染相关疾病,如有症状和无症状的ARC(“AIDS related complex”,艾滋病相关性综合征),或用于当怀疑暴露于HIV病毒时。
在作治疗用途时,化合物适于与可作药用的赋形剂和载体制剂。用于经口、肠胃外或吸入施用的适当形式有例如胶囊、粉末、颗粒、栓剂、溶液、悬液、糖浆、乳剂、注射溶液、喷雾溶液或悬液。药物组合物按照常规技术制剂,所述常规技术描述在例如Remington药物科学手册(Remington’s Pharmaceutical Science Handbook),Mack出版公司(MackPub.Co.),纽约,美国,第十七版。
剂量随疾病的严重性、患者的总体状况和年龄的不同而变化,且每千克体重的剂量通常为以单一剂量或多个剂量施用的1到1000毫克化合物,优选的剂量为从1到100mg/Kg。
本发明化合物也可以与其它目前可获得的抗HIV治疗剂联用。作为实例有HIV蛋白酶抑制剂(如沙奎那韦(saquinavir)、英地那韦(indinavir)、利托那韦(ritonavir)、奈费那韦(nelfinavir))、逆转录酶核苷和非核苷抑制剂(如叠氮胸苷、二脱氧胞苷和二脱氧肌苷)或其它整合酶抑制剂(参见例如10)。
因此,本发明还涉及联合制剂形式的药物组合物,所述药物组合物在治疗HIV感染时用于同时、单独或有序使用,其包含一种选自xenaldial、xenalamine和xenalic acid的化合物以及至少一种选自蛋白酶抑制剂、逆转录酶核苷或非核苷抑制剂、整合酶抑制剂的抗HIV剂。
下列实施例用于更详细地阐明本发明。
实施例1
材料
采用植入后第4天的静置管中淋巴母细胞培养物(接种物为200,000个细胞/毫升)。富含20%去补体的小牛血清培养基的乳清蛋白培养基作为培养用培养基(TC),且在感染培养物后,用补充有1%牛结晶白蛋白与2%小牛血清的199培养基作为维持培养基(TM)。所有培养基都加入青霉素(100U.I/ml)和链霉素(100μg/ml)。仅用199进行病毒稀释。
药物
xenalamine(对-(α-乙氧基-对-苯基苯乙酰-氨基)苯甲酸)、xenalicacid(对-(4-联苯-亚乙醛酰基(glyoxylidene))-氨基-苯甲酸)剂量为12.5微克;xenaldial(二水合-4-4’-双-联苯乙二醛)剂量为25微克。
每一药物的所用剂量为培养物所耐受的最大剂量,该剂量由以前实验所确定。
化合物用聚乙二醇200溶解,加热至100℃,加热15分钟。
抗病毒活性测定的一般方案
9.9毫升肉汤培养基,其中含有以悬液形式稀释至10-1的病毒,向其中加入0.10毫升含或不含化学治疗剂的聚乙二醇(xenaldial 2毫克,终浓度200μg/ml;xenalamine 23毫克,终浓度230μg/ml)。
所得悬液37℃孵育1小时,并反复搅拌。
孵育后,对每一悬液在肉汤培养基中进行对数梯度稀释(log·10)。随后将悬液接种至淋巴细胞培养物中(0.10毫升),以每稀释度8管为一组,以评估每一测试材料的LD50值。
结果报道在下表中(指示数字为三次实验的平均值)
起始贮液滴度** | 37℃孵育1小时后的病毒滴度** | 与200μg/mlxenaldial37℃孵育1小时后的病毒滴度** | 中和指数** | 与200μg/mlxenalamine37℃孵育1小时后的病毒滴度** | 中和指数** |
4.5 | 3.5 | 2.0 | 1.5 | 2.5 | 1.0 |
6.5 | 6.2 | 6.0 | 0.5 | 6.0 | 0.5 |
联苯酮醛衍生物的病毒失活作用在1到1.5个对数单位(U log·10)之间变化,且用xenaldial比用xenalamine稍明显。在所用实验条件下,观察到于37℃暴露于化合物1小时,病毒滴度已显著地减少(1个对数单位),LD50也是如此(与对照悬液相比)。
上表表明病毒对测试化合物的体外直接灭活作用不太敏感。
暴露于化合物后病毒致病活性的减少如下(以与对照相比对数值的百分率表示):
xenaldial-低病毒滴度42.8%;
xenaldial-高病毒滴度8.3%;
xenalamine-低病毒滴度28.5%;
xenalamine-高病毒滴度8.3%。
方法
以下方法用于计算在测试化合物存在时病毒的生长曲线:用1毫升含致细胞病变剂量的病毒液感染培养物,以获得约1∶1的LD50/细胞比。于36℃感染1小时,并用Hank平衡盐溶液反复洗涤,对照组用TM代替病毒液,而测试培养物用TM+药物代替病毒液。
间隔一定时间,从三种培养物中取出等份的试样,Hanks溶液洗涤,然后加入1毫升TM且-30℃冷冻。
实验的最后,将培养液融化并再次冷冻两次,合并每一等份试样,然后与冷冻前分离的相应液体同时滴定。
结果
结果绘制在图1-4,其中:
图1:xenalamine存在下的病毒生长曲线,xenalamine在感染后1小时加入培养物中,其加入剂量为12.5μg/ml。
图2:xenalic acid存在下的病毒生长曲线,xenalic acid在感染后1小时加入培养物中,其加入剂量为12.5μg/ml。
图3:xenaldial存在下的病毒生长曲线,xenaldial在感染后1小时加入培养物中,其加入剂量为25μg/ml。
图4:xenaldial存在下的病毒生长曲线,xenaldial在感染后1小时和48小时加入,其剂量为25μg/ml。
标绘图显示:
-在xenalamine处理的培养物中,液体中病毒的出现有约24小时的延迟。
-在xenaldial处理的培养物中,细胞内和细胞外病毒含量有显著变化;直至72小时,细胞内病毒量较对照低一个对数单位多;随后,减少程度逐渐降低直至实验终止时消失。由细胞释放的病毒与对照相比延迟24小时出现在液体中。当感染48小时后,用1毫升含25μg/ml的xenaldial的TM代替培养基时,观察到与对照相比对细胞内和细胞外病毒量的减少达到120小时。
实施例2
用淋巴细胞培养物测试xenaldial的HTLV IIIB-抑制活性。利用PCR法确定病毒抑制的百分率,方法如下:
DNA制备
使用400微升裂解液并在56℃/60秒和92℃/15秒孵育从5×104淋巴细胞中提取DNA。随后混合物室温冷却并于4℃保存。
探针
合成寡核苷酸SK19(41个碱基-对应于扩增的前病毒DNA的内在序列),以终浓度20μM溶解于水中,并用多核苷酸激酶和32P-ATP进行5’标记。
PCR
试剂:Taq多聚酶5U/μl,脱氧核苷酸(10mM pH7.0),KCl 2M,Tris-Cl 1M pH8.3,MgCl2 1M,明胶,引物15μM,探针15μM,32P-ATP,多核苷酸激酶10U/μl,DNA 1-3微克,EDTA 0.25M,蛋白酶K10mg/ml、SDS10%、乙酸铵2M、SSC 20×、Tris-硼酸盐-EDTA 10×、Tris-乙酸盐-EDTA 10×、上样缓冲液6×(溴酚蓝0.25%、二甲苯青0.25%、蔗糖40%、TRIS 10mM pH8.0)、裂解混合物(蛋白酶K 60μg/ml、NP-40 0.5%、Tween 20 0.5%、TRIS 5mM pH8.3、MgCl2 1.25mM、KCl 50mM);
试剂制备:核苷酸:每种核苷酸10mM,共125微升用水稀释至1毫升(终浓度为1.25mM);10×缓冲液:KCl 2M-250微升、TrisCl 1M pH8.3-100微升、MgCl2 1M-20微升、明胶-10毫克,用水稀释至1毫升。
寡核苷酸对:合成寡核苷酸SK38和SK39,纯化并以200-300μM的浓度溶解。
反应:10×混合缓冲液、核苷酸(1.25mM)、寡核苷酸引物SK38和SK39 15μM,裂解物,Taq多聚酶5U/μl;90℃/60秒变性,55℃/30秒退火,72℃/30秒聚合;重复循环30次。
结果报道在下表中:
xenaldial 0.001-5μM-HTLV IIIB | |||
药物浓度-μM | 平均OD | 经稀释校正的平均OD | 抑制百分率 |
未加药物的病毒 | 3740 | 374000 | - |
0.001 | 2096 | 209600 | 44% |
0.01 | 2654 | 265400 | 30% |
0.1 | 3300 | 330000 | 12% |
1 | 3144 | 314400 | 16% |
5 | 3630 | 363000 | 42% |
xenaldial 10-100μM-HTLV IIIB | |||
药物浓度-μM | 平均OD | 经稀释校正的平均OD | 抑制百分率 |
未加药物的病毒 | 2610 | 261000 | - |
10 | 3948 | 394800 | - |
20 | 1941 | 194100 | 26% |
40 | 3324 | 332400 | - |
60 | 1094 | 109400 | 59% |
100 | 610 | 61000 | 77% |
参考文献
1.HIV-1整合酶抑制剂的特征,M.S.T.HANSEN等人,生物学研究索尔克学会(The Salk Inst.For Biological Studies),La Jolla,CA。
2.含附加型复制起点的整合酶缺陷型慢病毒杂合载体的转导效率与基因表达,J.VARGAS等人,西奈山医学院(Mt Sinai Sch.Of Med.),纽约,NY。
3.存在于所有人中的HERV-K原病毒,M.BARBULESCU等人,爱因斯坦医学院(Albert Einstein Coll.Of Med.),Bronx,N.Y.和耶鲁大学医学院(Yale Univ.Sch.Of Med.),New Haven,CT。
4.一种用于研究HIV-1 Vpr功能的新诱导型系统,Y.ZHOU和L.RATNER,华盛顿大学医学院(Washington Univ.Sch.Of Med.),圣路易斯(St.Louis),MO。
5.人核苷酸切除修复基因HHR23A的裂殖酵母(Fission Yeast)直向同源基因(Rhp23)与HIV-1 Vpr相互作用的功能暗示,R.T.ELDER等人,Children′s Mem.Inst.For Ed.And Res.,西北大学医学院(Northwestern Univ,Med.Sch.)Chicago,IL。
6.HIV-1 Vpr的核输入与核输出,M.P.SHERMAN等人,Gladstone病毒学与免疫学研究所(Gladstone Inst.Of Virology andImmunology)和加州大学(Univ.of California),San Francisco。
7.HIV整合酶抑制剂:抗病毒活性与机制,D.J.HAZUDA,Merck研究实验室(Merck Res.Labs),West Point,PA。
8.化学治疗(Chemoterapia)9,1964,6:341-358。
9.Lorenzutti,G.等人:Studio comparativo di alcuni derivatichetoaldeidici in rapporto alla loro azione inattivante in vitro sul virusInfluenzale A-PR8 Boll.Soc.ital.Biol.Sper.40:1221(1964)。
10.科学(Science),2000,287卷:646-650。
Claims (6)
1.选自对-(α-乙氧基-对-苯基苯乙酰-氨基)苯甲酸、对-(4-联苯-亚乙醛酰基)-氨基-苯甲酸和二水合4-4’-双-联苯乙二醛的化合物的用途,其用于制备治疗人免疫缺陷病毒感染的药物。
2.如权利要求1所述的用途,其中所述化合物为二水合4-4’-双-联苯乙二醛。
3.如权利要求1或2所述的用途,其中所述药物用于预防或治疗人免疫缺陷病毒相关疾病。
4.如权利要求3所述的用途,其中所述人免疫缺陷病毒相关疾病为获得性免疫缺陷综合征。
5.用于治疗人免疫缺陷病毒感染的药物组合物,其包含有效量的选自对-(α-乙氧基-对-苯基苯乙酰-氨基)苯甲酸、对-(4-联苯-亚乙醛酰基)-氨基-苯甲酸和二水合4-4’-双-联苯乙二醛的化合物和其它目前可获得的抗人免疫缺陷病毒的药物。
6.根据权利要求5的组合物,其中所述其它目前可获得的抗人免疫缺陷病毒的药物选自蛋白酶抑制剂、逆转录酶抑制剂和整合酶抑制剂。
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- 2002-09-20 NO NO20024522A patent/NO20024522L/no not_active Application Discontinuation
- 2002-09-20 ZA ZA200207586A patent/ZA200207586B/xx unknown
Also Published As
Publication number | Publication date |
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WO2001070216A2 (en) | 2001-09-27 |
CA2403707A1 (en) | 2001-09-27 |
NO20024522D0 (no) | 2002-09-20 |
DE60104530T2 (de) | 2005-09-01 |
US20040058999A1 (en) | 2004-03-25 |
DE60104530D1 (de) | 2004-09-02 |
NO20024522L (no) | 2002-11-25 |
JP2003527419A (ja) | 2003-09-16 |
ITMI20000629A0 (it) | 2000-03-24 |
BR0109345A (pt) | 2002-12-17 |
ATE271859T1 (de) | 2004-08-15 |
WO2001070216A3 (en) | 2001-12-27 |
RU2002125444A (ru) | 2004-03-20 |
ITMI20000629A1 (it) | 2001-09-24 |
CN1419447A (zh) | 2003-05-21 |
EP1267858B1 (en) | 2004-07-28 |
AU2001263803A1 (en) | 2001-10-03 |
ZA200207586B (en) | 2003-09-22 |
IT1318424B1 (it) | 2003-08-25 |
ES2225550T3 (es) | 2005-03-16 |
MXPA02009173A (es) | 2003-03-12 |
EP1267858A2 (en) | 2003-01-02 |
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