CN1916167A - 过氧化物酶体增殖物激活受体的调节 - Google Patents
过氧化物酶体增殖物激活受体的调节 Download PDFInfo
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- CN1916167A CN1916167A CNA2006101098017A CN200610109801A CN1916167A CN 1916167 A CN1916167 A CN 1916167A CN A2006101098017 A CNA2006101098017 A CN A2006101098017A CN 200610109801 A CN200610109801 A CN 200610109801A CN 1916167 A CN1916167 A CN 1916167A
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Abstract
治疗与过氧化物酶体增殖物激活受体相关疾病的方法,通过给需要的受治疗者施用有效量的15-酮基前列腺素-Δ13-还原酶调节剂。还公开了一种鉴别化合物具有抑制该还原酶活性的方法,以及一种通过给受治疗者施用有效量的还原酶抑制剂降低血糖水平的方法。
Description
对相关申请的交叉引用
依据35U.S.C.§119(e),本申请要求于2005年8月12日提交的美国临时申请系列号60/707,897的优先权,其全部内容在此引入作为参考。
背景技术
过氧化物酶体增殖物激活受体(PPARs)属于调节脂肪和葡萄糖代谢作用的核受体家族。已经有三种哺乳动物PPARs得到了鉴定,即PPAR-α、PPAR-γ和PPAR-Δ。通过饮食中脂肪酸或者它们的代谢衍生物进行激活,PPARs可以引发转录时间的级联,其导致脂肪和葡萄糖代谢改变。例如,通过激活,在脂肪组织中高表达的PPAR-γ促进葡萄糖摄取和降低血糖水平。
基于它们在脂肪和葡萄糖代谢中的作用,预示PPARs是以下疾病的治疗目标,例如II型糖尿病、肥胖病、血脂障碍、冠心病、炎性疾病和癌症。合成的PPAR-γ激动剂,即AVANDIA和ACTOS,已经在用于治疗II型糖尿病。另一种合成PPAR-α激动剂,即Fibrate,已经用于治疗血脂障碍(dyslipidemia)。参见Lehmann等人,J Biol Chem,(1995)270:12953-12956;Fruchart等人,Curr.Opin.Lipdol.(1999)10:245-257。然而,大多数PPAR治疗的效能有限并且具有显著的副作用。
需要研制经调节PPAR活性来控制脂肪和葡萄糖代谢的更有效的药物。
发明内容
本发明涉及在受治疗者中经调节PPAR活性来治疗PPAR相关疾病的方法。
在本发明的一方面,本发明特征是还原15-酮基前列腺素而不还原白三烯B4的分离多肽PGR3/ZADH2。前列腺素(PG)是一类特征为中心环和不同不饱和度侧链的生理调节剂。15-酮基前列腺素的实例包括但不限于15-酮基PGE2、15-酮基PGE1、15-酮基PGF2α和15-酮基PGF1α。
在另一方面,本发明特征为与上述多肽特异性结合的抗体。上述抗体,多克隆抗体或者单克隆抗体,可与上述多肽片断结合。
在另一方面,本发明特征为用于抑制具有15-酮基前列腺素-Δ13-还原酶活性的多肽的双链核糖核酸(dsRNA),以及编码它的DNA载体。15-酮基前列腺素-Δ13-还原酶是指通过还原前列腺素Δ13双键将15-酮基前列腺素催化为13,14-二氢-15-酮基前列腺素的酶。15-酮基前列腺素-Δ13-还原酶的实例包括15-酮基前列腺素-Δ13-还原酶/白三烯B412-羟基脱氢酶(PGR/LTB4DH)、锌结合乙醇脱氢酶1(PGR2/ZADH1)和锌结合乙醇脱氢酶2(PGR3/ZADH2)。双链核糖核酸包含两条多聚核糖核酸链。第一条链含有与编码15-酮基前列腺素-Δ13-还原酶的核酸19至49位连续核苷酸相同的序列。第二条链与第一条链互补。优选,dsDNA的至少一个末端具有悬突的1至4个核苷酸。在一个实施例中,第一链含有SEQ ID NO:9或10,或其片断。15-酮基前列腺素-Δ13-还原酶可以是PGR/LTB4DH、PGR2/ZADH1或PGR3/ZADH2。
在另一方面,本发明特征在于治疗PPAR相关疾病的方法,例如II型糖尿病、肥胖、血脂障碍、冠心病、炎性疾病和癌症。该方法包括给受治疗者施用有效量的PGR3/ZADH2调节剂。PGR3/ZADH2调节剂是指影响PGR3/ZADH2活性或表达的分子或分子复合物。调节剂可以是15-酮基前列腺素。其也可是抑制剂,压制PGR3/ZADH2的活性或表达,例如大分子抑制剂(如上述的dsRNA)或小分子抑制剂(如四羟基黄酮、三羟基黄酮、2-羟基-三甲氧基查耳酮、2-羟基-苄基肉桂酸酯或苯甲基羟基肉桂酸酯)。小分子抑制剂的实例包括下述的化合物1-49。
化合物1 化合物2 化合物3
化合物4 化合物5 化合物6
化合物7 化合物8 化合物9
化合物10 化合物11 化合物12
化合物13 化合物14 化合物15
化合物16 化合物17 化合物18
化合物19 化合物20 化合物21
化合物22 化合物23 化合物24
化合物25 化合物26 化合物27
化合物28 化合物29 化合物30
化合物31 化合物32 化合物33
化合物34 化合物35 化合物36
化合物37 化合物38 化合物39
化合物40 化合物41 化合物42
化合物43 化合物44 化合物45
化合物46 化合物47 化合物48
化合物49
在其它方面,本发明特征在于治疗与PPAR相关疾病的方法。该方法包括给需要的受治疗者施用有效量的式(I)化合物:
在式(I)中,R1和R2每个独立地是H、卤素、ORa、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳基;并且R3、R4、R5、R6、R7、R8、R9、R10、R11和R12每个独立地是H、卤素、ORb、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;或R4和R5连在一起成为C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;或R10和R11连在一起成为C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;其中Ra和Rb每个独立地是H、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基。
在式(I)化合物的亚组中,R1和R2每个独立地是H、与环戊基稠合的苯基或被杂芳香基取代的苯基。在式(I)化合物另一个亚组中,R1和R2是OH。
术语“烷基”是指饱和或不饱和的、直链或支链的烃基部分,例如-CH3、-CH2-CH=CH2、或支链-C3H7。术语“环烷基”是指饱和或不饱和的、非芳香性的环烃基部分,例如环己基或环己烯-3-基。术语“杂环烷基”是指具有至少一个环杂原子(如N、O或S)的饱和或不饱和、非芳香性的环部分,例如4-四氢吡喃基或4-吡喃基。术语“芳香基”是指具有一个或多个芳香环的烃基部分。芳香基部分的实例包括苯基(Ph)、亚苯基、萘基、亚萘基、芘基、蒽基和菲基。术语“杂芳香基”是指具有一个或多个芳香环的部分,该芳香环含有至少一个杂原子(如N、O或S)。杂芳香基的实例包括呋喃基、亚呋喃基(furylene)、芴基(fluorenyl)、吡咯基、噻吩基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、异喹啉基和吲哚基。
除非另有说明,此处所提及的烷基、烯基、杂烯基、环烷基、杂环烷基、芳香基和杂芳香基包括饱和和不饱和部分。在环烷基、杂环烷基、芳香基和杂芳香基上可能的取代基包括,但不限于,C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C8环烷基、C5-C8环烯基、C1-C10烷氧基、芳香基、芳香氧基、杂芳香基、杂芳香氧基、氨基、C1-C10烷基氨基、C1-C20二烷基氨基、芳香氨基、二芳香基氨基、羟基、卤素、硫、C1-C10硫烷基、硫代芳香基、C1-C10磺酰烷基、磺酰芳香基、酰氨基、氨酰基、氨基硫酰基、脒基、胍基、脲基、氰基、硝基、酰基、硫酰基、酰氧基、羧基和羧酸酯。在其它方面,烷基、烯基或杂烯基可能的取代基包括所有上述的取代基,除了C1-C10烷基、C2-C10烯基和C2-C10炔基。环烷基、杂环烷基、芳香基和杂芳香基也可彼此稠合。
在另一方面,本发明特征在于治疗与PPAR相关疾病的方法,其通过给需要的受治疗者施用有效量的式(II)化合物:
在式(II)中,R1、R2、R3、R4、R5、R6、R7、R8、R9和R10每个独立地是H、OR、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;其中R是H、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香烷基或杂芳香烷基。在式(II)化合物的一个亚组中,R1、R2、R3、R4、R5、R6、R7、R8、R9和R10每个独立地是H或OH。
仍在另一方面,本发明特征在于治疗与PPAR相关疾病的方法,其通过给需要的受治疗者施用有效量的式(III)化合物:
在式(III)中,R1是C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基、杂芳香基、ORa、NRaRb或SRa;并且R2、R3、R4、R5和R6每个独立地是H、卤素、ORc、NRcRd、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;其中Ra、Rb、Rc和Rd每个独立地是H、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基。在式(III)的化合物亚组中,R1可以是被卤素、OR、NO2或C1-C10烷基取代的苯基,其中R是H或C1-C10烷基。在式(III)化合物的另一个亚组中,R1可以是ORa、NRaRb或SRa,其中Ra是被苯基取代的C1-C10烷基,苯基可任选地被CF3、F或OH取代,并且Rb是H。在式(III)化合物的另一个亚组中,R1是杂芳香基或被C(O)R取代的C1-C10烷基,其中R是H或C1-C10烷基。
降低受治疗者血糖水平的方法也处在本发明范围内。该方法包括给受治疗者施用有效量的上述PGR3/ZADH2抑制剂之一。抑制剂可压制PGR3/ZADH2的活性或表达。
本发明进一步的特征在于鉴定化合物具有抑制PGR3/ZADH2活性的方法。抑制是指压制PGR3/ZADH2的活性或表达。该方法包括提供含有PGR3/ZADH2系统,化合物与该系统接触,测定PGR3/ZADH2活性,并且将该活性与相同条件下不存在化合物所获得的进行比较。在一个实施方案中,该系统是含有表达PGR3/ZADH2基因的细胞,并且通过测量该基因的表达活性来测定活性。在另一个实施方案中,该系统是含有PGR3/ZADH2的无细胞溶液,并且通过测量无细胞溶液中PGR3/ZADH2酶活性来测量活性。
在下面的描述中,将列出本发明一种或多种实施方案的细节。从说明书和从权利要求书中,本发明的其它特征、目的和优点是显而易见的。
具体实施方式
本发明是基于发现15-酮基前列腺素-Δ13-还原酶3(PGR3/ZADH2),其为15-酮基前列腺素-Δ13-还原酶家族的成员。意外地发现PPAR地活性可通过它的底物和抑制剂来控制。这些底物和抑制剂可用于治疗与PPAR相关疾病,例如II型糖尿病、肥胖、血脂障碍、冠心病、炎性疾病和癌症。
在本发明范围内关注SEQ ID NO:1分离人多肽或其可还原15-酮基前列腺素的功能等效物。下面显示的是氨基酸序列(SEQ ID NO:1),以及编码核苷酸序列(即SEQ ID NO:2)。
1 M L R L V P T G A R A I V D M S Y A R H
1 ATGCTGCGGCTGGTGCCCACCGGGGCCCGGGCCATCGTGGACATGTCGTACGCCCGCCAC
21 F L D F Q G S A I P Q A M Q K L V V T R
61 TTCCTGGACTTCCAGGGCTCCGCCATTCCCCAAGCCATGCAGAAGCTGGTGGTGACCCGG
41 L S P N F R E A V T L S R D C P V P L P
121 CTGAGCCCCAACTTCCGCGAGGCCGTCACCCTGAGCCGGGACTGCCCGGTGCCGCTCCCC
61 G D G D L L V R N R F V G V N A S D I N
181 GGGGACGGAGACCTCCTCGTCCGGAACCGATTTGTTGGTGTTAACGCATCTGACATCAAC
81 Y S A G R Y D P S V K P P F D I G F E G
241 TATTCAGCAGGCCGCTATGACCCCTCAGTTAAGCCTCCCTTTGACATAGGTTTCGAAGGC
101 I G E V V A L G L S A S A R Y T V G Q A
301 ATTGGGGAGGTGGTGGCCCTAGGCCTCTCTGCTAGTGCCAGATACACAGTTGGCCAAGCT
121 V A Y M A P G S F A E Y T V V P A S I A
361 GTGGCTTACATGGCACCTGGTTCTTTTGCTGAGTACACAGTTGTGCCTGCCAGCATTGCA
141 T P V P S V K P E Y L T L L V S G T T A
421 ACTCCAGTGCCCTCAGTGAAACCCGAGTATCTTACCCTGCTGGTAAGTGGCACCACCGCA
161 Y I S L K E L G G L S E G K K V L V T A
481 TACATCAGCCTGAAAGAGCTCGGAGGACTGTCGGAAGGGAAAAAAGTTTTGGTGACAGCA
181 A A G G T G Q F A M Q L S K K A K C H V
541 GCAGCTGGGGGAACGGGCCAGTTTGCCATGCAGCTTTCAAAGAAGGCAAAGTGCCATGTA
201 I G T C S S D E K S A F L K S L G C D R
601 ATTGGAACCTGCTCTTCTGATGAAAAGTCTGCTTTTCTGAAATCTCTTGGCTGTGATCGT
221 P I N Y K T E P V G T V L K Q E Y P E G
661 CCTATCAACTATAAAACTGAACCCGTAGGTACCGTCCTTAAGCAGGAGTACCCTGAAGGT
241 V D V V Y E S V G G A M F D L A V D A L
721 GTCGATGTGGTCTATGAATCTGTTGGGGGAGCCATGTTTGACTTGGCTGTAGACGCCCTG
261 A T K G R L I V I G F I S G Y Q T P T G
781 GCTACGAAAGGGCGCTTGATAGTAATAGGGTTTATCTCTGGCTACCAAACTCCTACTGGC
281 L S P V K A G T L P A K L L K K S A S V
841 CTTTCGCCTGTGAAAGCAGGAACATTGCCAGCCAAACTGCTCAAGAAATCTGCCAGCGTA
301 Q G F F L N H Y L S K Y Q A A M S H L L
901 CAGGGCTTCTTCCTGAACCATTACCTTTCTAAGTATCAAGCAGCCATGAGCCACTTGCTC
321 E M C V S G D L V C E V D L G D L S P E
961 GAGATGTGTGTGAGCGGAGACCTGGTTTGTGAGGTGGACCTTGGAGATCTGTCTCCAGAG
341 G R F T G L E S I F R A V N Y M Y M G K
1021 GGCAGGTTTACTGGCCTGGAGTCCATATTCCGTGCTGTCAATTATATGTACATGGGAAAA
361 N T G K I V V E L P H S V N S K L SEQ ID NO:1
1081 AACACTGGAAAAATTGTAGTTGAATTACCTCACTCTGTCAACAGTAAGCTGTAA SEQ ID NO:2
分离的小鼠多肽或其可还原15-酮基前列腺素的功能等效物,相当于15-酮基前列腺素也在本发明范围内。下面显示的是小鼠多肽氨基酸序列(SEQ ID NO:3),以及编码核苷酸序列(即SEQ ID NO:4)。
SEQ ID NO:3
MLRLAAAGARAIVDMSYARHFLDFQGSAIPRTMQKLVVTRLSPNFHEAVTLRRDCPVPLPGDGDLLVRNRFVGINASDINYSAGRYDPSLKPPFDIGFEGIGEVVALGLSASARYTVGQAVAYMAPGSFAEYTVVPASIAIPMPSVKPEYLTMLVSGTTAYLSLEELGELSEGKKVLVTAAAGGTGQFAVQLSKIAKCHVIGTCSSDEKAAFLKSIGCDRPINYRTEPVETVLKQEYPEGVDVVYESVGGAMFDLAVDALATKGRLIVIGFISGYQSPTGLSPIKAGVLPTKLLKKSASLRGFFLNHYFSKYQAAMERLLELYARGDLVCEVDLGHLAPDGRFIGLESVFQAVDYMYTGKNTGKLVVELPHPVSSKL
SEQ ID NO:4
at gctgaggctg gcggccgccg gggcccgagc catcgtggac atgtcgtacg
53 cccgtcactt cctggacttc cagggctccg ccatcccccg aaccatgcag aagctggtgg
113 tgacccggct gagccctaac ttccacgagg ccgtcaccct gcgccgggac tgcccagtgc
173 cgctccccgg ggacggagac ctcctcgtcc ggaaccgatt cgttggtatt aacgcatctg
233 acatcaacta ttcggctggc cgctacgacc cgtccctgaa gccacccttt gacataggtt
293 ttgaagggat tggtgaggtg gtggccttag gcctctctgc tagtgctagg tacacagtgg
353 gccaggctgt ggcttatatg gctcctggtt cctttgctga gtatacagtg gtgcctgcta
413 gcattgcaat tcccatgcct tcagtgaaac cagagtatct caccatgctg gttagtggca
473 ccactgcata cctcagcctg gaagagcttg gggaactgtc agaagggaag aaagttctgg
533 tcacagcagc cgctgggggc acaggccagt ttgctgtgca gctttccaag atagccaagt
593 gccacgttat cggaacctgc tcctcagacg aaaaggcagc ttttctgaaa tcaattgggt
653 gtgatcggcc catcaactac agaacagagc ctgtggagac ggttctgaag caggagtacc
713 ctgaaggcgt tgacgtagtc tatgagtctg ttgggggagc catgtttgac ctggctgtgg
773 atgccttggc caccaaaggg cgcttgatag tgattgggtt tatctctggc taccaaagcc
833 ctacaggact ctcaccaata aaagcgggag ttttgccaac caagctcctg aagaagtcgg
893 ccagcctcag gggtttcttt ctgaaccact acttctccaa gtaccaggct gccatggaac
953 gtttgctgga gctgtacgct cgtggggacc tggtgtgtga ggtggacctg ggacacctgg
1013 ctccggatgg aaggttcatt ggcctggagt ccgtgtttca ggctgtcgac tatatgtaca
1073 cggggaaaaa tactgggaag cttgttgttg agttaccaca ccctgtcagc agtaagctgt
1133 ga
分离的多肽是指基本不含天然相关分子的多肽,即以干重计它至少是75%纯(即包括75%至100%之间的任意数字)。可以用任意合适的标准方法测量纯度,例如通过柱层析、聚酰胺凝胶电泳或HPLC分析。本发明的分离多肽可从天然来源得到纯化,可利用重组DNA技术或通过化学方法得到生产。术语“功能等效物”是指具有还原15-酮基前列腺素功能的SEQ NO:1或SEQ NO:2多肽的变体,如具有一个或多个点突变、插入、删除、截短或它们的组合的蛋白质。在一个实施方案中,本发明的分离多肽或其功能等效物包含与SEQ NO:1或SEQ NO:3至少80%相同序列(包括如85%、95%或100%或80%至100%之间的任意数字)。它可以是融合蛋白。
15-酮基前列腺素-Δ13-还原酶活性是指将15-酮基前列腺素酶促转化为13,14-二氢-15-酮基前列腺素。具体活性的测定如下:37℃将待分析的10μg蛋白样本孵育于反应缓冲液中,该缓冲液含有0.1M Tris-HCl(pH7.4)、0.5mM NADH和0.57mM 15-酮基PGE2。37℃将反应在黑暗中进行10分钟,加入700μl缓冲液中止反应,该缓冲液含有50mM邻苯二甲酸氢钾,pH3.0,以及1%吐温20。使用200μl成色试剂氧化任何未反应的NADPH,成色试剂中包含790μM氯化碘基硝基四唑、60μM phenazene methosulfate和1%吐温20。使用ELISA平板读数器在490nm处测量吸收值。使用含有连续稀释量的NADPH的反应缓冲液绘制标准曲线。至少90nmol/min.mg蛋白质的具体活性表明多肽具有15-酮基前列腺素-Δ13-还原酶活性。
上述的核苷酸多肽,即SEQ ID NO:2或SEQ ID NO:4,可用于表达本发明的多肽。核苷酸序列是指DNA分子(如acDNA或基因组DNA)、RNA分子(如mRNA)或DNA或RNA类似物。DNA或RNA类似物可从核苷酸类似物得到合成。核酸分子可以是单链或双链,但优选双链。出于表达蛋白质的目的,可将核酸有效地连接至合适的调控序列以得到表达载体。载体是指能将其它核酸转移至已被连接的其它核酸上的分子。载体能够自主复制或整合于宿主DNA。载体的实例包括质粒、粘粒和病毒载体。载体可包括以适合核酸在宿主细胞中表达的形式的核苷酸序列。优选载体包括一种或多种有效连接待表达核苷酸序列的调节序列。“调节序列”包括启动子、增强子、和其它表达调控元件(如多腺苷酸化信号)。调节序列包括那些直接构成性表达的核苷酸序列,以及组织特异性调节和/或诱导序列。表达载体的设计取决于对一些因素,如待转化细胞的选择、所期望的蛋白质的表达水平等的选择。表达载体可引入宿主细胞以产生本发明多肽。包含上述核酸的宿主细胞也处于本发明范围内。实例包括大肠杆菌细胞(E.coli cells)、Sf9插入细胞(如使用杆状病毒表达载体)、酵母细胞或哺乳动物细胞。参见例如如Goeddel,(1990)Gene Expression Technology:Methods inEnzymology 185,Academic Press,San Diego,CA。为生产本发明多肽,人们可在允许本发明核苷酸编码多肽表达的条件下在培养基中培养宿主细胞,并从所培养细胞或细胞培养基中纯化多肽。作为选择,核苷酸序列可在体外转录和翻译,例如使用T7启动子调节序列和T7多聚酶。
上述的多肽可用于在动物中产生抗体。可以理解的是抗体也可从多肽片断中产生。在动物中产生单克隆和多克隆抗体及其片断的方法是本领域公知的。参见例如Harlow和Lane,(1988)Antibodies:A LaboratoryManual,Cold Spring Harbor Laboratory,New York。术语“抗体”包括完整的分子以及它的片断,例如Fab、F(ab′)2、Fv、scFv(单链抗体)和dAb(域抗体;Ward等人(1989)Nature,341,544)。
总之,本发明的多肽可与载体蛋白偶联(如KLH)、与佐剂混合和注射于宿主动物。在该动物中产生的抗体可用多肽亲和层析来纯化。通常使用的宿主动物包括兔、小鼠、豚鼠和大鼠。可用于增加免疫反应的多种佐剂取决于宿主种类,并且该佐剂包括Freund′s佐剂(完全和不完全)、矿务凝胶如氢氧化铝、表面活性剂如溶血卵磷脂、多元醇普卢兰尼克、多聚阴离子、多肽、油乳胶、锁孔青贝血蓝蛋白(keyhole limpet hemocyanin)和二硝基酚。人用佐剂包括卡介苗(BCG)和短小棒状杆菌。
多克隆抗体、抗体分子异质群存在于经免疫受治疗者的血清中。对本发明多肽的单克隆抗体、抗体同质群可使用标准杂交瘤技术制备(参见例如Kohler等人(1975)Nature 256,495;Kohler等人(1976)Eur J Immunol6,511;Kohler et al.(1976)Eur J Immunol 6,292;和Hammerling等人(1981)Monoclonal Antibodies and T Cell Hybridomas,Elsevier,N.Y.)。尤其是,通过用培养基中连续的细胞系来提供产生抗体分子的任意技术,可获得单克隆抗体,例如描述于Kohler等人(1975)Nature 256,495和美国专利第4,376,110号;the human B-cell hybridoma technique(Kosbor等人(1983)Immunol Today 4,72;Cole等人(1983)Proc.Natl.Acad.Sci.USA 80,2026和the EBV-hybridoma technique(Cole等人(1983)Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,Inc.,pp.77-96).这些抗体可以是任意的免疫球蛋白类型,包括IgG、IgM、IgE、IgA、IgD及它们的亚类。产生本发明单克隆抗体的杂交瘤可在体外或体内培养。在体内产生高滴度抗体的能力使得其成为特别有用的生产方法。
另外,可使用研发用于生产“嵌合抗体”的技术。参见,例如Morrison等人(1984)Proc.Natl.Acad.Sci.USA 81,6851;Neuberger等人(1984)Nature 312,604;和Takeda等人(1984)Nature 314:452。嵌合抗体是其不同部分来源于不同动物种类的分子,例如具有来源于鼠单克隆抗体的可变区和人免疫球蛋白恒定区的抗体。作为选择,描述用于产生单链抗体的技术(美国专利第4,946,778和4,704,692号)可被适合于产生单链Fv抗体的噬菌体文库。通过经氨基酸桥将Fv区域的重链和轻链片断连接起来,形成单链抗体。此外,通过已知的技术可产生抗体片断。例如,这些片断包括,但不限于,通过胃蛋白酶降解抗体分子产生的F(ab′)2片断,和通过还原F(ab′)2片断的二硫桥产生的Fab片断。也可通过本领域公知的方法人源化抗体。例如,带有所期望特定结合的单克隆抗体可商业性人源化(Scotgene,Scotland;和Oxford Molecular,Palo Alto,Calif.)。完全的人抗体,例如在转基因动物中表达的也是本发明的特征(参见,例如Green等人(1994)Nature Genetics 7,13;和美国专利第5,545,806和5,569,825号)。
双链核糖核酸(dsRNA)也包括在本发明的范围内。该dsRNA可用于抑制PGR3/ZADH2的表达。因此,通过给受治疗者施用dsRNA可治疗PPAR相关疾病。术语“dsRNA”是指通过降解靶RNA序列沉默基因表达的双链核糖核酸,该过程称作RNA干扰(RNAi)。在大量的动物模型(包括线虫、斑马鱼和小鼠胚胎)和其它生物体系(包括外植的鸡神经细胞和哺乳动物细胞培养物)中RNA已用于沉默基因表达。参见WO99/32619、WO00/44914、WO00/44914、WO00/44895、WO00/63364和WO01/36646A1。
本发明的RNA可通过本领域公知的的技术来合成。参见例如Caruthers等人,1992,Methods in Enzymology 211,3-19,Wincott等人,1995,Nucleic Acids Res.23,2677-2684,Wincott等人,1997,Methods Mol.Bio.74,59,Brennan等人,1998,Biotechnol Bioeng.,61,33-45,和Brennan,美国专利第6,001,311号。RNA也可从表达载体被转录,并使用标准技术分离。也可使用本领域公知的方法将本发明的或载体传输至靶细胞中。参见例如Akhtar等人,1992,Trends Cell Bio.2,139。例如,可以使用脂质体、水凝胶、环糊精、生物可降解纳米胶囊或生物粘附性微球来将其引入细胞。作为选择,通过直接注射或使用输液泵可局部传输RNA或载体。其它的方法包括多种运输和传递系统的使用,例如使用偶合并生物可降解的聚合物。
本发明特征也在于通过调节PGR3/ZADH2活性或表达来治疗PPAR相关疾病的方法。术语“治疗”是指给患者施用一种或多种上述的PGR3/ZADH2调节剂,即PGR3/ZADH2底物或抑制剂,这些患者患有PPAR相关疾病、该疾病的症状或对该疾病的遗传缺陷,目的在于提供治疗作用,如治愈、缓解、改变、影响、改善或预防PPAR相关疾病、该疾病症状或对该疾病的遗传缺陷。“有效量”是指在待治疗患者上要求产生治疗作用的量。PGR3/ZADH2的底物包括15-酮基PGE2、15-酮基PGE1.15-酮基PGF2α、15-酮基PGF1α,和它们的结构类似物。
PPAR相关疾病(或紊乱或病症)的实例包括,但不限于,II型糖尿病、高血糖症、低葡萄糖耐受、X综合症、胰岛素抵抗、肥胖、脂质紊乱、血脂障碍、高甘油三酸酯血症、高胆固醇血症、低HDL水平、高LDL水平、动脉粥样硬化(以及它的后遗症例如心绞痛、跛行、心肌梗死或中风)、血管再狭窄、应激性肠综合症、炎性疾病、(例如炎性肠病、风湿性关节炎、Crohn氏病、溃疡性大肠炎、骨关节炎、多发性硬化症、哮喘、脉管炎、缺血/再灌注损伤、冻疮或成人呼吸窘迫综合征)、胰腺炎、神经变性疾病、视网膜病、肿瘤病症、癌症(例如前列腺、胃、乳腺、膀胱、肺或结肠癌,或脂肪细胞癌如脂肪肉瘤)、血管发生、Alzheimer病、皮肤紊乱(如痤疮、银屑病、皮肤炎、湿疹或角化病)、高血压、卵巢雄激素过多症、骨质疏松症和骨质减少。
为了治疗PPAR相关疾病,可以给需要治疗的受治疗者施用含有PGR3/ZADH2调节剂和药用可接受载体的药用组合物。其可口服或经静脉输注,或皮下、肌内、鞘内、腹膜内、直肠内、阴道内、鼻内、胃内、气管内或肺内注射或植入。
药用组合物可以是在无毒可接受稀释剂或溶液中的溶液或悬浮液,例如在1,3-丁二醇中的溶液。在可接受的载体或溶液中,所使用的是甘露醇、水、Ringer’s溶液和等渗氯化钠溶液。另外,不挥发性油通常用作溶液或悬浮介质(例如合成的甘油单酯或甘油二酯)。脂肪酸,例如油酸及其甘油酯衍生物用于注射剂的制备,例如天然药用可接受油,如橄榄油或蓖麻油,尤其是它们的聚氧乙烯型。这些油溶液或悬浮液也可含有长链醇稀释剂或分散剂、羧甲基纤维素或类似的分散剂。其它常规所用的表面活性剂例如吐温或司盘,或用于制备药用可接受固体、液体或其它剂量形式中通常使用的其它类似的乳化剂或生物利用度增强剂可用于制剂目的。
所需要的剂量取决于对施用途径、制剂性质、受治疗者疾病性质、受治疗者大小、体重、表面积、年龄和性别、待施用的其它药物、主治医生的判断的选择。合适的剂量为0.01-100.0mg/kg。考虑到可获得组合物的多样性和多种施用路径的不同效率,可以期望所需剂量的宽变化。使用标准的最优化试验途径如本领域众所周知的,来调整那些剂量水平的变化。在合适传输载体中的胶囊化组合物(如聚合型微粒或植入装置)可增加传输的效率,尤其是口服传输。
利用常规方法,上述的药用组合物可配制成不同使用途径的剂量形式。例如,其可配制成胶囊、密封凝胶、或用于口服的片剂。胶囊可含有任何标准药用可接受物质,例如明胶或或纤维素。通过压制组合物与固体载体和润滑剂的混合物,按照常规方法可配制片剂。固体载体的实例包括淀粉和糖皂土(sugar bentonite)。组合物也可以硬壳片剂或含有粘合剂(如乳糖或甘露醇)、常规填充剂和压片剂的胶囊的形式来施用。药用组合物可经非肠道途径施用。非肠道剂量形式的实例包括活性药物的水溶液、活性药物的等渗生理盐水和5%葡萄糖,或其它众所周知的药用可接受赋形剂。环糊精或其它本领域所公知的增溶剂,可用作用于传输治疗药物的药用辅料。
可在体内和体外评估上述药用组合物的有效性。简单的说,可测试药用组合物体外抑制PGR3/ZADH2活性或表达的能力。对于体内研究,药用组合物可给动物注射(如小鼠模型),然后获得治疗效果。基于结果,可决定合适的剂量范围和施用途径。
本发明进一步的特征在于鉴定抑制PGR3/ZADH2活性或表达的化合物的方法。根据多肽的三维构象可设计化合物,例如使用计算机建模程序,并使用本领域公知的方法合成。也可使用文库筛选来鉴别,或使用任意大量方法与本领域公知的文库方法组合来获得。合适的文库包括:多肽文库、类肽文库(具有多肽功能,但含有新的、对酶降解有抵抗性的非肽骨架的分子的文库)、空间可寻址平行固相或液相文库、通过重叠合法或亲和层析选择获得的文库、“一珠一化合物”文库和抗体文库。参见例如Zuckermann等人(1994)J.Med.Chem.37,2678-85;Lam(1997)Anticancer Drug Des.12,145;Lam等人(1991)Nature 354,82;Houghten等人(1991)Nature354,84;和Songyang等人(1993)Cell 72,767。在现有技术中有分子文库合成方法的实例,例如DeWitt等人(1993)Proc.Natl.Acad.Sci.USA90,6909;Erb等人(1994)Proc.Natl.Acad.Sci.USA 91,11422;Zuckermann等人(1994)J.Med.Chem.37,2678;Cho等人(1993)Science261,1303;Carrell等人(1994)Angew.Chem.Int.Ed.Engl.33,2059;Carell等人(1994)Angew.Chem.Int.Ed.Engl.33,2061和Gallop等人(1994)J.Med.Chem.37,1233.Libraries of compounds may bepresented in solution(例如,Houghten(1992)Biotechniques 13,412-421),或在珠上(Lam(1991)Nature 354,82-84),芯片(Fodor(1993)Nature 364,555-556),细菌(美国专利第5,223,409号),芽孢(美国专利第5,223,409号),质粒(Cull等人(1992)Proc.Natl.Acad.Sci.USA 89,1865-1869),或噬菌体(Scott和Smith(1990)Science 249,386-390;Devlin(1990)Science 249,404-406;Cwirla等人(1990)Proc.Natl.Acad.Sci.USA 87,6378-6382;Felici(1991)J.Mol.Biol.222,301-310;和美国专利第5,223,409号).
下面具体的实施例将仅作为说明性解释,并且无论以任何方式不限制公开内容的其它部分。不需要进一步详细阐述,可以相信本领域技术人员可以,基于此处的描述,利用本发明至最充分的程度。所有此处引用的出版物在此以其全部内容在此引入作为参考。
实施例1新15-酮基前列腺素-Δ13-还原酶的鉴别
对应于GenBank存取号NM146090和BC033780基因编码区的cDNA全长序列分别被称作小鼠PGR3/ZADH2和人PGR3/ZADH2。使用从3T3-L1脂肪细胞中提取的mRNA通过PCR制备小鼠PGR3/ZADH2 cDNA,并通过T4连接酶(Promega)连接至pGEM-T简单载体(Promega)。用于获得小鼠和人PGR3/ZADH2的正向/反向引物序列如下:
小鼠:
正向5’-ATTGGATCCCAAATGCTGAGGCTGGCGGCC-3’(SEQ ID NO:5)
反向5’-ACGATGAATTCACAGCTTACTGCTGACAG-3’(SEQ ID NO:6)
人:
正向5’-CGCGGATCCTTATGCTGCGGCTGGTGCCCAC-3’(SEQ ID NO:7)
反向5’-CCGGAATTCTTACAGCTTACTGTTGACAGAGTG-3’(SEQ ID NO:8))。
上面显示的是人PGR3/ZADH2(SEQ ID NO:1)和小鼠SEQ ID NO:3推导的氨基酸序列。发现小鼠PGR3/ZADH2与人ZADH1(GenBank存取号.:NM152444)同源,但没有显著相似性。
在3T3-L1细胞中脂肪形成期间PGR3/ZADH2表达增加。在诱导脂肪形成后的第3天观察到最高表达。在这个时间点,观察到脂滴在脂肪细胞中广泛地累积。在完全分化的脂肪细胞中检测到PGR3/ZADH2蛋白的最高水平。也发现在脂肪形成的早期显著地诱导PPAR-γ。
也测定了PGR3/ZADH2的组织分布。在脂肪组织中其高度表达。网膜脂肪中PGR3/ZADH2 mRNA的量纯合型和杂合型db/db小鼠显著高于野生型小鼠。
在大肠杆菌中按照标准程序以GST融合蛋白重组表达人和小鼠PGR3/ZADH2蛋白。因此所获得的重组PGR3/ZADH2蛋白用于测定底物特异性和酶动力学。
酶活性测定如下。37℃,10μg重组小鼠或人PGR3/ZADH2蛋白孵育于反应缓冲液中,该缓冲液含有0.1M Tris-HCL(pH7.4)、0.5mM NADH和0.57mM15-酮基PGE2。37℃将反应在黑暗中进行10分钟,并加入700μl缓冲液中止反应,该缓冲液含有50mM邻苯二甲酸氢钾,pH3.0,以及1%吐温20。使用200μl成色试剂氧化任何未反应的NADPH,成色试剂中包含790μM氯化碘基硝基四唑、60μM phenazene methosulfate和1%吐温20。使用ELISA平板读数器在490nm处测量吸收值。使用含有连续稀释量的NADPH的反应缓冲液绘制标准曲线。
使用刚才描述的方法测定PGR3/ZADH2底物特异性,除了15-酮基前列腺素被6种前列腺素中的每一个,三个下游代谢物中的每种或白三烯B4替换。15-酮基PGE1、15-酮基PGF1α和15-酮基PGF2α特异性与PGR-3反应。通过对比,从6-酮基PGF1、PGF2、11b-PGF2、13,14-二氢-15-酮基PGF2、13,14-二氢-15-酮基PGD2、13,14-二氢-15-酮基PGE2或白三烯B4中没有测定到明确活性。
也研究了在人Hep3B细胞中,PGR-3/ZADH2表达对调节PPAR-γ转录的作用,其表达内源性人PPAR-α和PPAR-β。在Hep3B细胞中发现PGR-3/ZADH2的过度表达抑制PPAR介导的转录激活。甚至在Hep3B细胞被PPAR-γ激动剂,即BRL49653,刺激后,转录活性也被抑制。从3T3-L1细胞中也得到类似结果。
实施例2前列腺素
研究了在脂肪细胞中前列腺素对PPAR-γ活性的作用。用可诱导细胞分化的介质治疗后,从第2天至第4天在脂肪形成期间用14μM15-酮基PGE2,13,14-二氢-15-酮基PGE2,15-酮基PGF2α,13,14-二氢-15-酮基PGF2α,或4.5μM BRL49653,PPAR-γ激动剂处理3T3-L1细胞。参见Forman等人Cell(1995)83:803-812。在第6天,脂滴的聚集使得用于观察的油红0着色。在与BRL49653相似的水平15-酮基PGE2有效地增强了脂肪形成。被诱导分化2天后,用报告基因转染3T3-L1细胞。
15-酮基PGE2和15-酮基PGF2α显著增强内源性PPAR活性。
通过对比,相应的下游代谢物,即13,14-二氢-15-酮基PGE2和13,14-二氢-15-酮基PGF2α,没有增加PPAR活性。
连同PPAR-α、PPAR-γ配体结合域或PPAR-Δ融合酵母GAL4DNA结合域,将荧光素酶报告基因转染至3T3-L1细胞。15-酮基PGE2和15-酮基PGF2α激活PPAR-γ,并以较小的程度激活PPAR-α。
也检查了15-酮基PGE2诱导脂肪形成特异性,PPAR-γ靶基因,即IRS-1和-2,蛋白质表达的能力。当用胰岛素和地塞米松,而不仅用甲基异丁基黄嘌呤(MIX)处理时,在3T3-L1细胞中检测到基本量的PPAR-γ和PPAR-γ2。15-酮基PGE2和MIX同胰岛素和地塞米松的加入显著地增强了PPAR-γ和PPAR-γ2的表达。15-酮基PGE2和BRL49653强烈地诱导aP2的表达,脂肪细胞特异性标记,甚至MIX不存在下。胰岛素和地塞米松存在时,BRL49653治疗显著地增加了IRS-2表达。15-酮基PGE2增强表达至与MIX相似的水平。胰岛素/地塞米松或MIX诱导IRS-1表达。包括15-酮基PGE2和BRL49653的PPAR-γ配体不增加IRS-1的量。
实施例3PGR3/ZADH2小分子抑制剂
表达了重组人PGR3/ZADH2蛋白,并检测了它的酶活性。与鼠PGR3/ZADH2相似,重组人PGR3/ZADH2具有15-酮基前列腺素-Δ13-还原酶活性,并催化将15-酮基前列腺素转化为13,14-二氢-15-酮基前列腺素。
测试化合物1-49对PGR3/ZADH2活性的抑制作用。这些化合物是商业可获得的(例如来自Sigma-Aldrich,St.Louis,MO)或可从本领域公知方法制备。按照上面描述的方法进行抑制分析。向反应混合物中加入不同浓度的PGR3/ZADH2抑制剂,并于37℃孵育2小时。
更明确的是,向PGR3/ZADH2酶反应体系中加入50μM化合物8,12,13和27,以及25μM三氟苄基-2-羟基肉桂酸(化合物22),并测量酶还原15-酮基前列腺素的能力。
表1
%活性 | 无抑制剂 | 化合物12 | 化合物13 | 化合物8 | 化合物27 |
人PGR3/ZADH2 | 100 | 27.5 | 51.1 | 25.6 | 91.1 |
小鼠PGR3/ZADH2 | 100 | 6.4 | 37.1 | 11.4 | 87.4 |
表2
%活性 | 无抑制剂 | 三氟苄基-2-羟基肉桂酸 |
人PGR3/ZADH2 | 100 | 29.6 |
小鼠PGR3/ZADH2 | 100 | 27.4 |
如表1和2所示,利用上面5种化合物抑制了PGR3/ZADH2的15-酮基前列腺素-Δ13-还原酶活性。进一步,发现浓度为50μM时化合物1-7、9-11、14-26和28-49都抑制活性超过20%。
实施例4PGR3/ZADH2抑制剂对胰岛素敏感性的作用
如下检测了两种上述PGR3/ZADH2抑制剂,即化合物12和28,对胰岛素敏感性的作用。以同上述相同的方式诱导分化了3T3-L1细胞。按照Finga等人(Endocrinology 134:728-735)描述的方法,通过测量对2-脱氧-D-[3H]葡萄糖摄取进行了葡萄糖转运分析。向细胞中加入1.67M抑制剂或45nMPPAR-γ激动剂,即Avandia。
10M细胞松弛素B用于测量葡萄糖摄取背景水平。100nM胰岛素用于刺激葡萄糖摄取。在分化的3T3-L1细胞中单独的胰岛素治疗以超过10倍增加葡萄糖摄取。在任两种PGR3/ZADH2抑制剂存在下,葡萄糖摄取增加了30倍。已发现这些抑制剂增加葡萄糖摄取的能力与AVANDIA相当。
在db/db小鼠中检测了PGR3/ZADH2抑制剂对降低血糖的作用。雌性db/db小鼠以4只/笼圈养(10-11周龄,C57BLKS/J-m+/+Lepdb,The JacksonLaboratory)。向10只小鼠腹膜注5mg/kg三氟苄基-2-羟基肉桂酸(化合物22)、PGR3抑制剂(小鼠#1-#6)或安慰剂(小鼠#7-#10,相对于体液的最终浓度:PBS中0.2%DMSO/0.7%乙醇),每天2次,持续7天。在第一次注射前和最后注射后18小时获取来自小鼠后眶窦的血样。利用电极型血糖测量仪(HORIBA,AntSense II,日本)测量血样中葡萄糖水平。结果汇总于下表3。最后栏显示%抑制,其代表(B.G..前-B.G..后)/B.G.前×100%。结果表明PGR-3抑制剂显著降低小鼠血糖水平。
表3
实施例5RNA干扰
在3T3-L1前脂肪细胞中用RNA干扰方法沉默PGR3/ZADH2表达。为产生编码目标为PGR3/ZADH2的干扰RNAs的载体,使用标准方法合成含有5’-GAT CCG TGC CAC GTT ATC GGA ACC TTC AAG AGA GGT TCC GAT AAC GTGGCA CTT TTT TGG AAA-3’(SEQ ID NO:9;正向引物)和AGC TTT TCC AAA AAAGTG CCA CGT TAT CGG AAC CTC TCT TGA AGG TTC CGA TAA CGT GGC ACG-3’(SEQID NO:10;反向引物)的寡核苷酸。然后将它们退火,并引入线性siRNA表达载体,pSilencerTM neo(catalog# 5764,Ambion)。随后利用电穿孔将siRNA表达载体导入3T3-L1前脂肪细胞中。利用G418筛选法分离稳定的转染克隆。然后利用标准RT-PCR检测在这些权利要求中PGR3/ZADH2 mRNA水平。发现PGR3/ZADH2 mRNA转录水平受到抑制。
按照Forman等人,Cell(1995)83:803-812描述的方法,使用上述的克隆进行基于PPAR报告子的分析。发现在这些克隆中PPAR-γ转录活性得到增强。这些结果表明利用RNA干扰经沉默PGR3/ZADH2表达可调节PPAR-γ活性,并因此治疗PPAR相关疾病。
其他实施方案
在本说明书中公开的所有特征可以以任何组合的形式来组合。在本说明书中公开的每一个特征可以被起相同、相当或相似目的可替换的特征来替代。因此,除非另有明确说明,所公开的每一个特征仅是一类相当或相似特征的实施例。
从上面的描述,本领域技术人员能确定本发明的基本特征,以及在不偏离本发明精神和范围下,能将本发明作出多种变化和修饰适应于多种用法和病症。因此,其它实施方案也在本权利要求书范围内。
序列表
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<120>过氧化物酶体增殖物激活受体的调节
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Val Thr Leu Ser Arg Aso Cys Pro Val Pro Leu Pro Gly Asp Gly Asp
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Tyr Ser Ala Gly Arg Tyr Asp Pro Ser Val Lys Pro Pro Phe Asp Ile
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gag atg tgt gtg agc gga gac ctg gtt tgt gag gtg gac ctt gga gat 1008
Glu Met Cys Val Ser Gly Asp Leu Val Cys Glu Val Asp Leu Gly Asp
325 330 335
ctg tct cca gag ggc agg ttt act ggc ctg gag tcc ata ttc cgt gct 1056
Leu Ser Pro Glu Gly Arg Phe Thr Gly Leu Glu Ser Ile Phe Arg Ala
340 345 350
gtc aat tat atg tac atg gga aaa aac act gga aaa att gta gtt gaa 1104
Val Asn Tyr Met Tyr Met Gly Lys Asn Thr Gly Lys Ile Val Val Glu
355 360 365
tta cct cac tct gtc aac agt aag ctg taa 1134
Leu Pro His Ser Val Asn Ser Lys Leu
370 375
<210>3
<211>377
<212>PRT
<213>小鼠(Mus musculus)
<400>3
Met Leu Arg Leu Ala Ala Ala Gly Ala Arg Ala Ile Val Asp Met Ser
1 5 10 15
Tyr Ala Arg His Phe Leu Asp Phe Gln Gly Ser Ala Ile Pro Arg Thr
20 25 30
Met Gln Lys Leu Val Val Thr Arg Leu Ser Pro Asn Phe His Glu Ala
35 40 45
Val Thr Leu Arg Arg Asp Cys Pro Val Pro Leu Pro Gly Asp Gly Asp
50 55 60
Leu Leu Val Arg Asn Arg Phe Val Gly Ile Asn Ala Ser Asp Ile Asn
65 70 75 80
Tyr Ser Ala Gly Arg Tyr Asp Pro Ser Leu Lys Pro Pro Phe Asp Ile
85 90 95
Gly Phe Glu Gly Ile Gly Glu Val Val Ala Leu Gly Leu Ser Ala Ser
100 105 110
Ala Arg Tyr Thr Val Gly Gln Ala Val Ala Tyr Met Ala Pro Gly Ser
115 120 125
Phe Ala Glu Tyr Thr Val Val Pro Ala Ser Ile Ala Ile Pro Met Pro
130 135 140
Ser Val Lys Pro Glu Tyr Leu Thr Met Leu Val Ser Gly Thr Thr Ala
145 150 155 160
Tyr Leu Ser Leu Glu Glu Leu Gly Glu Leu Ser Glu Gly Lys Lys Val
165 170 175
Leu Val Thr Ala Ala Ala Gly Gly Thr Gly Gln Phe Ala Val Gln Leu
180 185 190
Ser Lys Ile Ala Lys Cys His Val Ile Gly Thr Cys Ser Ser Asp Glu
195 200 205
Lys Ala Ala Phe Leu Lys Ser Ile Gly Cys Asp Arg Pro Ile Asn Tyr
210 215 220
Arg Thr Glu Pro Val Glu Thr Val Leu Lys Gln Glu Tyr Pro Glu Gly
225 230 235 240
Val Asp Val Val Tyr Glu Ser Val Gly Gly Ala Met Phe Asp Leu Ala
245 250 255
Val Asp Ala Leu Ala Thr Lys Gly Arg Leu Ile Val Ile Gly Phe Ile
260 265 270
Ser Gly Tyr Gln Ser Pro Thr Gly Leu Ser Pro Ile Lys Ala Gly Val
275 280 285
Leu Pro Thr Lys Leu Leu Lys Lys Ser Ala Ser Leu Arg Gly Phe Phe
290 295 300
Leu Asn His Tyr Phe Ser Lys Tyr Gln Ala Ala Met Glu Arg Leu Leu
305 310 315 320
Glu Leu Tyr Ala Arg Gly Asp Leu Val Cys Glu Val Asp Leu Gly His
325 330 335
Leu Ala Pro Asp Gly Arg Phe Ile Gly Leu Glu Ser Val Phe Gln Ala
340 345 350
Val Asp Tyr Met Tyr Thr Gly Lys Asn Thr Gly Lys Leu Val Val Glu
355 360 365
Leu Pro His Pro Val Ser Ser Lys Leu
370 375
<210>4
<211>1134
<212>DNA
<213>小鼠(Mus musculus)
<400>4
atgctgaggc tggcggccgc cggggcccga gccatcgtgg acatgtcgta cgcccgtcac 60
ttcctggact tccagggctc cgccatcccc cgaaccatgc agaagctggt ggtgacccgg 120
ctgagcccta acttccacga ggccgtcacc ctgcgccggg actgcccagt gccgctcccc 180
ggggacggag acctcctcgt ccggaaccga ttcgttggta ttaacgcatc tgacatcaac 240
tattcggctg gccgctacga cccgtccctg aagccaccct ttgacatagg ttttgaaggg 300
attggtgagg tggtggcctt aggcctctct gctagtgcta ggtacacagt gggccaggct 360
gtggcttata tggctcctgg ttcctttgct gagtatacag tggtgcctgc tagcattgca 420
attcccatgc cttcagtgaa accagagtat ctcaccatgc tggttagtgg caccactgca 480
tacctcagcc tggaagagct tggggaactg tcagaaggga agaaagttct ggtcacagca 540
gccgctgggg gcacaggcca gtttgctgtg cagctttcca agatagccaa gtgccacgtt 600
atcggaacct gctcctcaga cgaaaaggca gcttttctga aatcaattgg gtgtgatcgg 660
cccatcaact acagaacaga gcctgtggag acggttctga agcaggagta ccctgaaggc 720
gttgacgtag tctatgagtc tgttggggga gccatgtttg acctggctgt ggatgccttg 780
gccaccaaag ggcgcttgat agtgattggg tttatctctg gctaccaaag ccctacagga 840
ctctcaccaa taaaagcggg agttttgcca accaagctcc tgaagaagtc ggccagcctc 900
aggggtttct ttctgaacca ctacttctcc aagtaccagg ctgccatgga acgtttgctg 960
gagctgtacg ctcgtgggga cctggtgtgt gaggtggacc tgggacacct ggctccggat 1020
ggaaggttca ttggcctgga gtccgtgttt caggctgtcg actatatgta cacggggaaa 1080
aatactggga agcttgttgt tgagttacca caccctgtca gcagtaagct gtga 1134
<210>5
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物
<400>5
attggatccc aaatgctgag gctggcggcc 30
<210>6
<211>29
<212>DNA
<213>人工序列
<220>
<223>引物
<400>6
acgatgaatt cacagcttac tgctgacag 29
<210>7
<211>31
<212>DNA
<213>人工序列
<220>
<223>引物
<400>7
cgcggatcct tatgctgcgg ctggtgccca c 31
<210>8
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物
<400>8
ccggaattct tacagcttac tgttgacaga gtg 33
<210>9
<211>63
<212>DNA
<213>人工序列
<220>
<223>引物
<400>9
gatccgtgcc acgttatcgg aaccttcaag agaggttccg ataacgtggc acttttttgg 60
aaa 63
<210>10
<211>63
<212>DNA
<213>人工序列
<220>
<223>引物
<400>10
agcttttcca aaaaagtgcc acgttatcgg aacctctctt gaaggttccg ataacgtggc 60
acg 63
Claims (39)
1、一种分离多肽,包含SEQ ID NO:1或SEQ ID NO:3或其功能等效物,其中该多肽还原15-酮基前列腺素。
2、权利要求1的分离多肽,包含与SEQ ID NO:1或SEQ ID NO:3至少90%相同的序列。
3、权利要求2的分离多肽,包含与SEQ ID NO:1或SEQ ID NO:3至少80%相同的序列。
4、权利要求1的分离多肽,其中多肽是SEQ ID NO:1或3。
5、权利要求4的分离多肽,其中15-酮基前列腺素是15-酮基PGE2、15-酮基PGE1、15-酮基PGF2α或15-酮基PGF1α。
6、权利要求5的分离多肽,其中15-酮基前列腺素是15-酮基PGE2。
7、一种抗体,其中该抗体与权利要求1的多肽特异性结合。
8、权利要求7的抗体,其中该抗体是单克隆抗体。
9、权利要求7的抗体,其中该抗体是SEQ ID NO:1。
10、一种治疗与过氧化物酶体增殖物激活受体相关疾病的方法,包括给需要的受治疗者施用有效量的PGR3/ZADH2调节剂。
11、权利要求10的方法,其中调节剂是15-酮基前列腺素。
12、权利要求11的方法,其中15-酮基前列腺素是15-酮基PGE2、15-酮基PGE1、15-酮基PGF2α或15-酮基PGF1α。
13、权利要求12的方法,其中15-酮基前列腺素是15-酮基PGE2。
14、权利要求10的方法,其中调节剂是PGR3/ZADH2抑制剂。
15、权利要求14的方法,其中抑制剂是权利要求28的dsDNA。
16、权利要求14的方法,其中抑制剂是四氢黄酮、三氢黄酮、2-羟基-三甲氧基查耳酮或2-羟基-苄基肉桂酸酯或它们的衍生物。
17、权利要求14的方法,其中抑制剂是化合物1-49中的一种。
18、权利要求14的方法,其中抑制剂是抗体。
19、权利要求10的方法,其中PPAR相关疾病是II型糖尿病、肥胖、血脂障碍、冠心病、炎性疾病或癌症。
20、权利要求19的方法,其中PPAR相关疾病是II型糖尿病、肥胖、血脂障碍或冠心病。
21、权利要求20的方法,其中PPAR相关疾病是II型糖尿病。
22、一种在受治疗者中降低血糖水平的方法,包括给患者施用有效量的PGR-3/ZADH2抑制剂。
23、权利要求22的方法,其中所述抑制剂是四氢黄酮、三氢黄酮、2-羟基-三甲氧基查耳酮或2-羟基-苄基肉桂酸酯。
24、权利要求22的方法,其中抑制剂是权利要求28的dsRNA或化合物1-49中的化合物。
25、鉴别化合物具有抑制PGR3/ZADH2活性的方法,包括提供含有PGR3/ZADH2的系统,将化合物与该系统接触,测定PGR3/ZADH2活性,以及将该活性与相同条件下不合所述化合物时获得的活性进行比较。
26、权利要求25的方法,其中系统是含有表达PGR3/ZADH2基因的细胞,并且通过测量基因的表达活性来测定活性。
27、权利要求25的方法,其中系统是含有PGR3/ZADH2的无细胞溶液,并且通过测量PGR3/ZADH2的酶活性来测定活性。
28、用于抑制PGR3/ZADH2表达的双链核糖核酸(dsRNA),包含多聚核糖核酸的第一条链和多聚核糖核酸的第二条链,其中第一条链含有与编码PGR3/ZADH2的核酸中19-49连续核苷酸相同的序列,并且第二条链与第一条链互补。
29、权利要求28的双链核糖核酸,其中第一条链含有SEQ ID NO:9或10,或它们的片断。
30、一种治疗PPAR相关疾病的方法,包括给需要的患者施用有效量的式(I)化合物:
其中
R1和R2每个独立地是H、卤素、ORa、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳基;并且
R3、R4、R5、R6、R7、R8、R9、R10、R11、和R12每个独立地是H、卤素、ORb、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;或R4和R5连在一起成为C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;或R10和R11连在一起成为C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;其中Ra和Rb每个独立地是H、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基。
31、权利要求30的方法,其中R1和R2每个独立地是H、与环苯基骈合的苯基或被杂芳香基取代的苯基。
32、权利要求30的方法,其中R3和R12每个是OH。
33、治疗PPAR相关疾病的方法,包括给需要的患者施用有效量的式(II)化合物:
其中
R1、R2、R3、R4、R5、R6、R7、R8、R9和R10每个独立地是H、OR、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香基或杂芳香基;
其中R是H、C1-C10烷基、C3-C20环烷基、C3-C20杂环烷基、芳香烷基或杂芳香烷基。
34、权利要求33的方法,其中R1、R2、R3、R4、R5、R6、R7、R8、R9和R10每个独立地是OH。
36、权利要求35的方法,其中R1可以是被卤素、OR、NO2或C1-C10烷基取代的苯基,其中R是H或C1-C10烷基。
37、权利要求35的方法,其中R1可以是ORa、NRaRb或SRa,其中Ra是被苯基取代的C1-C10烷基,苯基可任选地被CF3、F或OH取代,并且Rb是H。
38、权利要求35的方法,其中R1是杂芳香基或被C(O)R取代的C1-C10烷基,其中R是H或C1-C10烷基。
Applications Claiming Priority (2)
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US70789705P | 2005-08-12 | 2005-08-12 | |
US60/707,897 | 2005-08-12 |
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CN1916167A true CN1916167A (zh) | 2007-02-21 |
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CNA2006101098017A Pending CN1916167A (zh) | 2005-08-12 | 2006-08-14 | 过氧化物酶体增殖物激活受体的调节 |
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US (1) | US20070037193A1 (zh) |
EP (1) | EP1803809A3 (zh) |
JP (1) | JP2007061093A (zh) |
KR (1) | KR20080014936A (zh) |
CN (1) | CN1916167A (zh) |
AR (1) | AR054909A1 (zh) |
AU (1) | AU2006203479A1 (zh) |
BR (1) | BRPI0603206A (zh) |
CA (1) | CA2553115A1 (zh) |
CO (1) | CO5780135A1 (zh) |
IL (1) | IL177407A0 (zh) |
MX (1) | MXPA06009161A (zh) |
NO (1) | NO20063652L (zh) |
SG (1) | SG130141A1 (zh) |
TW (1) | TW200741003A (zh) |
ZA (1) | ZA200606661B (zh) |
Cited By (5)
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CN101948458A (zh) * | 2010-09-07 | 2011-01-19 | 中国药科大学 | 具有抗肿瘤活性的黄芩素衍生物及在医药上的应用 |
CN102964322A (zh) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | 异黄酮或类黄酮脂肪醚类衍生物、其制备方法和医药用途 |
CN107496414A (zh) * | 2017-09-21 | 2017-12-22 | 上海华堇生物技术有限责任公司 | 柽柳黄素的药物用途 |
CN112645922A (zh) * | 2020-12-24 | 2021-04-13 | 中国人民解放军空军军医大学 | 香豆素类化合物、制备方法及应用 |
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WO2009026657A1 (en) * | 2007-08-29 | 2009-03-05 | The University Of Sydney | Flavonoid ppar agonists |
DE112009001301T5 (de) * | 2008-05-28 | 2011-06-09 | Basf Se | Mittel und Verfahren zur Beurteilung einer erhöhten Peroxisomenproliferation |
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US8918198B2 (en) * | 2009-01-21 | 2014-12-23 | George Atanasoff | Methods and systems for control of a surface modification process |
EA015364B1 (ru) * | 2009-03-18 | 2011-06-30 | Учреждение Российской Академии Наук Институт Элементоорганических Соединений Им. А.Н. Несмеянова Ран (Инэос Ран) | 6,6'-диизопропил-8,8'-диметил-2,2'-динитро-3,3'-бис(трифторметил)- 3н,3'н-[9,9']ди[бензо(f)хроменил]-5,10,5',10'-тетраол, обладающий противоопухолевой и противогрибковой активностью, и способ его получения |
US9752191B2 (en) * | 2009-07-09 | 2017-09-05 | The Scripps Research Institute | Gene expression profiles associated with chronic allograft nephropathy |
JP7029777B2 (ja) * | 2016-03-28 | 2022-03-04 | 国立大学法人金沢大学 | アンドロゲン依存性又は非依存性前立腺癌細胞の抑制用の組成物及びそれを含有する前立腺癌の医薬製剤 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2543550B1 (fr) * | 1983-04-01 | 1985-08-09 | Cortial | Nouveaux derives de la tetrahydroxy-3', 4',5,7 flavone, leur methode de preparation et leur emploi therapeutique |
US4587260A (en) * | 1984-06-21 | 1986-05-06 | Warner-Lambert Company | Dibenzalacetone and benzylcinnamate as non-steroidal anti-inflammatory compounds and compositions thereof |
ATE174221T1 (de) * | 1990-05-01 | 1998-12-15 | R Tech Ueno Ltd | Behandlung von pankreaskrankheit mit 15-keto- prostaglandin e-derivaten |
CA2046069C (en) * | 1990-07-10 | 2002-04-09 | Ryuji Ueno | Treatment of inflammatory diseases with 15-keto-prostaglandin compounds |
JP2000500490A (ja) * | 1995-11-17 | 2000-01-18 | ファルマシア・アンド・アップジョン・カンパニー | 糖尿病治療用の4−ヒドロキシクマリン−3−カルボキシアミド |
JP2003517288A (ja) * | 1999-05-20 | 2003-05-27 | インサイト・ゲノミックス・インコーポレイテッド | オキシドレダクターゼタンパク質 |
CN1443070A (zh) * | 2000-03-24 | 2003-09-17 | 苏坎波公司 | 包含15-酮基-前列腺素或其衍生物的编程性细胞死亡抑制组合物 |
EP1402026A2 (en) * | 2000-04-18 | 2004-03-31 | Millennium Pharmaceuticals, Inc. | 39228, a human alcohol dehydrogenase and uses therefor |
AU2001255696A1 (en) * | 2000-04-27 | 2001-11-07 | Geron Corporation | Telomerase inhibitors and methods of their use |
US7326734B2 (en) * | 2003-04-01 | 2008-02-05 | The Regents Of The University Of California | Treatment of bladder and urinary tract cancers |
-
2006
- 2006-08-08 US US11/500,579 patent/US20070037193A1/en not_active Abandoned
- 2006-08-08 EP EP06291283A patent/EP1803809A3/en not_active Withdrawn
- 2006-08-09 TW TW095129257A patent/TW200741003A/zh unknown
- 2006-08-10 IL IL177407A patent/IL177407A0/en unknown
- 2006-08-10 AR ARP060103503A patent/AR054909A1/es not_active Application Discontinuation
- 2006-08-10 SG SG200605449-8A patent/SG130141A1/en unknown
- 2006-08-10 JP JP2006218187A patent/JP2007061093A/ja active Pending
- 2006-08-11 CA CA002553115A patent/CA2553115A1/en not_active Abandoned
- 2006-08-11 CO CO06079383A patent/CO5780135A1/es not_active Application Discontinuation
- 2006-08-11 AU AU2006203479A patent/AU2006203479A1/en not_active Abandoned
- 2006-08-11 ZA ZA200606661A patent/ZA200606661B/xx unknown
- 2006-08-11 MX MXPA06009161A patent/MXPA06009161A/es not_active Application Discontinuation
- 2006-08-11 NO NO20063652A patent/NO20063652L/no not_active Application Discontinuation
- 2006-08-12 KR KR1020060076462A patent/KR20080014936A/ko not_active Application Discontinuation
- 2006-08-14 CN CNA2006101098017A patent/CN1916167A/zh active Pending
- 2006-08-14 BR BRPI0603206-0A patent/BRPI0603206A/pt not_active Application Discontinuation
Cited By (7)
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CN101948458A (zh) * | 2010-09-07 | 2011-01-19 | 中国药科大学 | 具有抗肿瘤活性的黄芩素衍生物及在医药上的应用 |
CN101948458B (zh) * | 2010-09-07 | 2012-11-07 | 中国药科大学 | 具有抗肿瘤活性的黄芩素衍生物及在医药上的应用 |
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CN115894422A (zh) * | 2022-12-26 | 2023-04-04 | 上海中医药大学 | PPARγ激动剂及其组合和应用 |
Also Published As
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AR054909A1 (es) | 2007-07-25 |
KR20080014936A (ko) | 2008-02-15 |
SG130141A1 (en) | 2007-03-20 |
CO5780135A1 (es) | 2007-07-31 |
CA2553115A1 (en) | 2007-02-12 |
EP1803809A3 (en) | 2007-12-19 |
BRPI0603206A (pt) | 2007-05-15 |
MXPA06009161A (es) | 2007-03-21 |
JP2007061093A (ja) | 2007-03-15 |
IL177407A0 (en) | 2006-12-31 |
ZA200606661B (en) | 2008-05-28 |
EP1803809A2 (en) | 2007-07-04 |
TW200741003A (en) | 2007-11-01 |
US20070037193A1 (en) | 2007-02-15 |
NO20063652L (no) | 2007-02-13 |
AU2006203479A1 (en) | 2007-03-01 |
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