CN111699248A - 用于合成噻吩并吡啶化合物的混合二硫键缀合物的生物催化剂和方法 - Google Patents
用于合成噻吩并吡啶化合物的混合二硫键缀合物的生物催化剂和方法 Download PDFInfo
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- CN111699248A CN111699248A CN201980012798.2A CN201980012798A CN111699248A CN 111699248 A CN111699248 A CN 111699248A CN 201980012798 A CN201980012798 A CN 201980012798A CN 111699248 A CN111699248 A CN 111699248A
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- thienopyridine
- thiol
- mixed disulfide
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Abstract
本发明涉及以细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂合成噻吩并吡啶化合物的混合二硫键缀合物的方法,且属于化学合成领域。
Description
关于联邦资助研究或开发的声明
本发明是在美国国立卫生研究院(National Institutes of Health)授予的AA020090的政府支持下完成的。政府在本发明中拥有某些权利。
技术领域
本发明涉及以细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂合成噻吩并吡啶化合物的混合二硫键缀合物的方法,且属于化学合成领域。
引言
如之前所证实的,噻吩并吡啶类的混合二硫键缀合物是很有前途的抗血小板剂(参见,例如,Zhang,H.,et al.,(2016)J Pharmacol Exp Ther 359,11-17)。这些化合物是杂环硫醇与活性抗血小板剂噻吩并吡啶的缀合物。这样的活性抗血小板剂之一是氯吡格雷的药理活性代谢物(AM),(Z)-2-(1-((S)-1-(2-氯苯基)-2-甲氧基-2-氧亚基乙基)-4-巯基哌啶-3-亚基)乙酸在AM和杂环硫醇之间形成二硫键产生稳定的混合二硫键缀合物,其可以容易地在体内活化,从而快速且有效地抑制血小板聚集(参见,例如,Zhang,H.,et al.,(2016)J Pharmacol Exp Ther 359,11-17;Zhang,H.,et al.,(2014)Thromb.Haemost.112,1304-1311)。
尽管其具有优良的抗血小板性质,但噻吩并吡啶化合物及其二硫键缀合物的活性代谢物的化学合成一直颇具挑战性(参见,例如,Asai,F.,Sugidachi,K.,Ikeda,T.,Iwabuchi,H.,Kuroki,Y.,Inoue,T.,Iwamura,R.,and Shinbakawa,N.(2003)Cyclic aminocompounds.(Office,U.P.a.T.ed.,Sankyo Company,Limited,US;Shaw,S.A.,et al.,(2015)J Org Chem 80,7019-7032)。这些化合物的化学合成涉及多个步骤,且产率低。这至少部分是由于:1)AM在室温下的不稳定性。2)存在多个手性中心。在氯吡格雷的AM的情况下,它除了在C3-16处含有双键之外,还在C4和C7处含有两个手性中心,从而导致了8种立体异构体的组合。只有AM的7S和顺式双构型具有抗血小板活性。然而,将反式转换为顺式构型的效率非常低(参见,例如,Asai,F.,Sugidachi,K.,Ikeda,T.,Iwabuchi,H.,Kuroki,Y.,Inoue,T.,Iwamura,R.,and Shinbakawa,N.(2003)Cyclic amino compounds.(Office,U.P.a.T.ed.,Sankyo Company,Limited,US)。
之前已经证明,噻吩并吡啶化合物在肝微粒体(LM)中的代谢产生了AM和其混合二硫键缀合物(参见,例如,Zhang,H.,et al.,(2014)Thromb.Haemost.112,1304-1311)。然而,由于产物产率低和LM成本高,因此使用肝微粒体进行大规模合成是费用昂贵的。事实上,还没有可行的方法来生产用于药物开发和其他应用的大量的噻吩并吡啶化合物的混合二硫键缀合物。
因此,需要改进的方法来生产用于药物开发和其他应用的大量的噻吩并吡啶化合物的混合二硫键缀合物。
本发明解决了这一需求。
发明内容
氯吡格雷(Plavix)、噻氯匹啶(Ticlid)和普拉格雷(Effient)属于一类噻吩并吡啶基化合物,广泛用作预防心脏病发作和中风的抗血小板剂。然而,这些药物存在一些严重的缺点,包括反应不同、毒性和出血风险增加。这些缺点与它们都是需要通过多态细胞色素P450酶(P450s)的氧化生物活化的前药这一事实密切相关。
为了克服与噻吩并吡啶化合物(氯吡格雷(Plavix)、噻氯匹啶(Ticlid)和普拉格雷(Effient))相关的缺点,本发明提供了噻吩并吡啶化合物的混合二硫键缀合物。预期本发明的这样的噻吩并吡啶化合物的混合二硫键缀合物能够在内源性谷胱甘肽(GSH)的存在下产生活性噻吩并吡啶代谢物(例如,具有抗血小板活性的活性噻吩并吡啶代谢物),而不需要通过P450s的生物活化。这种方法不仅绕过了通过P450s的氧化生物活化过程,而且也规避了与噻吩并嘧啶基药物相关的许多缺点。例如,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物改善了给药一致性,因为从该缀合物产生活性代谢物是可预测的。此外,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物作为抗血小板剂降低了毒性,因为毒性反应代谢物不会通过硫醇交换反应产生。此外,本发明的噻吩并吡啶化合物的混合二硫键缀合物的治疗起效时间缩短了,这大大有益于经历急性心血管事件的患者。例如,氯吡格雷的标准方案要求持续给药患者3-5天,因为只有一小部分被摄取的药物会转化为活性代谢物。与之相比,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物将在少于30min内以高产率释放活性代谢物。此外,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物将具有相比活性代谢物优越的稳定性,并因此可用于定量生成体外基础和临床研究的活性代谢物。
因此,本发明涉及用基因工程生物催化剂高效合成高光学活性的噻吩并吡啶化合物的混合二硫键缀合物的方法,即在存在还原剂NADPH或NADH以及作为催化剂的细胞色素P450 BM3或CYP102A1的基因工程变体的情况下,通过混合2-氧亚基噻吩并吡啶和杂环硫醇,制备高光学活性的噻吩并吡啶化合物的混合二硫键缀合物的一步法方法。该方法操作简单,并且原料和试剂都是容易获得的。与现有技术方法相比,该方法以更高的产率选择性地产生缀合物的顺式立体异构体。
在某些实施方式中,本发明提供了突变型CYP102A1酶,该酶能够在还原剂的存在下催化2-氧亚基噻吩并吡啶和杂环硫醇之间的缀合。在一些实施方式中,在还原剂的存在下催化2-氧亚基噻吩并吡啶和杂环硫醇之间的缀合导致生成噻吩并吡啶化合物的混合二硫键缀合物。在一些实施方式中,在还原剂的存在下催化2-氧亚基噻吩并吡啶和杂环硫醇之间的缀合选择性地生成了噻吩并吡啶化合物的混合二硫键缀合物的顺式立体异构体。在一些实施方式中,还原剂是NADPH或NADH。
在一些实施方式中,酶包括与BM3的野生型氨基酸序列(SEQ ID NO:2;图4B)具有85%的同源性的氨基酸序列。在一些实施方式中,酶包括与BM3的野生型氨基酸序列(SEQID NO:2;图4B)具有90%的同源性的氨基酸序列。在一些实施方式中,酶包括与BM3的野生型氨基酸序列(SEQ ID NO:2;图4B)具有95%的同源性的氨基酸序列。在一些实施方式中,酶包括与BM3的野生型氨基酸序列(SEQ ID NO:2;图4B)具有99%的同源性的氨基酸序列。在一些实施方式中,酶包括具有在SEQ ID NO:2内的以下氨基酸突变中的一种或多种的氨基酸序列:A82F、L188Q、R47L、F87V、T365N、H116Q、K31T、S56R、A135S、V299D、I458F、P481H和W1046A。在一些实施方式中,酶包括具有表2中所列的一组特定突变的氨基酸序列。
在一些实施方式中,酶包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少85%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少90%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少95%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少99%的同源性的核酸。
在一些实施方式中,酶包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少85%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少90%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少95%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:3(突变型BM3cDNA;图4C)具有至少99%的同源性的核酸。在一些实施方式中,酶包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少100%的同源性的核酸。
在某些实施方式中,本发明提供了用于合成噻吩并吡啶化合物的混合二硫键缀合物的顺式立体异构体的方法,包括在还原剂的存在下混合2-氧亚基噻吩并吡啶部分、杂环硫醇部分和所述突变型CYP102A1酶。在一些实施方式中,还原剂是NADPH或NADH。在一些实施方式中,2-氧亚基噻吩并吡啶部分由下式表示:
;其中R1是氯或氟;其中R2是H、COOCH3或COCHCH2CH2。在一些实施方式中,杂环硫醇部分由R3-SH表示;其中R3选自3-硝基吡啶-2-硫醇、2-巯基吡啶、2-巯基-6-甲基吡啶、5-氯吡啶-2-硫醇、2-巯基-5-三氟甲基-吡啶、3-(三氟甲基)吡啶-2-硫醇、2-巯基吡啶-3-甲腈、4,6-二甲基-2-硫代-1,2-二氢吡啶-3-甲腈、2-喹啉硫醇、1-氨基-3-巯基异喹啉、6-氯哒嗪-3-硫醇和2,5-二甲基呋喃-3-硫醇。在一些实施方式中,混合发生在环境温度下。在一些实施方式中,混合发生的时间段在20至60分钟之间。在一些实施方式中,突变型CYP102A1酶包含在细菌胞质级分中。在一些实施方式中,突变型CYP102A1酶的量在大约0.1和1μM之间。在一些实施方式中,混合导致每升的2-氧亚基噻吩并吡啶部分、杂环硫醇部分、突变型CYP102A1酶和还原剂生成大约100mg的噻吩并吡啶化合物的混合二硫键缀合物的顺式立体异构体。
在某些实施方式中,本发明提供了包含2-氧亚基噻吩并吡啶部分、杂环硫醇部分和一种或多种所述突变型CYP102A1酶的试剂盒。
在一些实施方式中,试剂盒还包含还原剂。在一些实施方式中,还原剂是NADPH或NADH。在一些实施方式中,2-氧亚基噻吩并吡啶部分由以下表示其中R1是氯或氟;其中,R2是H、COOCH3或COCHCH2CH2。在一些实施方式中,杂环硫醇部分由R3-SH表示;其中R3选自3-硝基吡啶-2-硫醇、2-巯基吡啶、2-巯基-6-甲基吡啶、5-氯吡啶-2-硫醇、2-巯基-5-三氟甲基-吡啶、3-(三氟甲基)吡啶-2-硫醇、2-巯基吡啶-3-甲腈、4,6-二甲基-2-硫代-1,2-二氢吡啶-3-甲腈、2-喹啉硫醇、1-氨基-3-巯基异喹啉、6-氯哒嗪-3-硫醇和2,5-二甲基呋喃-3-硫醇。
在一些实施方式中,本发明提供了包含用所述方法生成的化合物和药学上可接受的载体的药物组合物。在一些实施方式中,其中药物组合物配置为用于静脉给药。
在某些实施方式中,本发明提供了治疗、改善或预防患者中的心血管疾病的方法,包括向所述患者给药治疗有效量的用所述方法生成的化合物。在一些实施方式中,给药选自由口服给药和静脉给药组成的组。在一些实施方式中,心血管疾病选自由冠状动脉疾病、周围血管疾病、动脉粥样硬化血栓形成和脑血管疾病组成的组。在一些实施方式中,化合物减少了血小板的聚集。在一些实施方式中,减少所述血小板的聚集通过与P2Y12受体不可逆结合而发生。在一些实施方式中,减少所述血小板的聚集通过阻断ADP受体而发生。在一些实施方式中,该方法还包括共同给药选自由以下组成的组的至少一种剂:HMG-CoA还原酶抑制剂、ACE抑制剂、钙通道阻滞剂、血小板聚集抑制剂、多不饱和脂肪酸、苯氧酸衍生物、胆汁酸螯合剂、抗氧化剂、血栓溶解剂和抗心绞痛剂。
附图说明
图1:氯吡格雷的混合二硫键缀合物的产物的HPLC分析。通过将2-氧亚基氯吡格雷、杂环硫醇、BM3和NADPH在25℃下混合20min进行反应。然后用等体积的含有1%甲酸的乙腈淬灭反应。通过HPLC分析反应混合物的5μl等分试样。以“S”表示的双峰是外消旋-2-氧亚基氯吡格雷的两个立体异构体,以星号表示的双峰代表期望产物。在254nm处观察洗脱。
图2:氯吡格雷的混合二硫键缀合物的产物的HPLC分析。通过将(±)-2-氧亚基氯吡格雷、杂环硫醇、大鼠LM和NADPH在25℃下混合20min进行反应。
图3:在BM3的存在下合成ClopNPT的产率。反应在25℃下进行。
图4A:野生型巨大芽孢杆菌(B.megaterium)细胞色素P-450:NADPH-P-450还原酶基因(参见,例如,登记号J04832)的1541至4690的野生型cDNA(SEQ ID NO:1)。
图4B:巨大芽孢杆菌细胞色素P-450:NADPH-P-450还原酶基因(参见,例如,登记号J04832)的野生型氨基酸序列(SED ID NO:2)。
图4C:细胞色素P450 BM3或CYP102A1的基因工程变体的优化的cDNA(SEQ ID NO:3)。
具体实施方式
本发明涉及作为催化剂的细胞色素P450 BM3或CYP102A1的基因工程变体,用该生物催化剂合成噻吩并吡啶化合物的混合二硫键缀合物的方法,以及用于治疗、改善和预防心血管疾病的相关疗法。
在开发本发明的实施方式的过程中进行的实验确定了使用细胞色素P450 BM3或CYP102A1的工程变体作为生物催化剂来立体选择性的和高效的合成噻吩并吡啶化合物的混合二硫键缀合物的方法。
因此,本发明涉及用基因工程生物催化剂高效合成高光学活性的噻吩并吡啶化合物的混合二硫键缀合物的方法,即在存在还原剂(例如NADPH或NADH)以及作为催化剂的细胞色素P450 BM3或CYP102A1的基因工程变体的情况下,通过混合2-氧亚基噻吩并吡啶和杂环硫醇,制备高光学活性的噻吩并吡啶化合物的混合二硫键缀合物的一步法方法。该方法操作简单,并且原料和试剂都是容易获得的。与现有技术方法相比,该方法以更高的产率选择性地产生缀合物的顺式立体异构体(例如,以远优于使用肝微粒体的产率产生顺式立体异构体)。
生物酶催化剂,诸如P450BM-3酶,在各种工业应用中得到越来越多的应用,从精细化学品、中间体、药物和药物代谢物的合成到有机化学污垢物和污染物的降解。利用定向进化或定点诱变的蛋白质工程,可用于分离已知酶的变体,这可能为其催化活性创造新的机会和应用。
来自巨大芽胞杆菌的P450BM-3(参见,例如,Miura,Y.,and Fulco,A.J.(1975)Biochim.Biophys.Acta 388,305-317)属于细胞色素P450酶的超家族。在各种基因序列数据库中,存在超过7,700个编码P450酶的基因。P450酶的命名已经系统化。该酶的超家族被称为CYP,接着用数字表示酶的家族(所以为CYP1、CYP51、CYP102等),这些被分为由字母表示的亚家族(所以为CYP1A、CYP101B等),并且每个亚家族成员用数字表示(所以为CYP1A1、CYP3A4、CYP101D3等)。编码CYP酶的基因用斜体表示,例如CYP101A1基因。P450BM-3被命名为CYP102A1,即它是CYP102家族的第一个成员。此后P450BM-3将采用系统名称CYP102A1。
CYP102A1(参见,例如,Miura,Y.,and Fulco,A.J.(1975)Biochim.Biophys.Acta388,305-317)是用于生物转化应用的一种极具吸引力的酶,因为它在催化方面可以自给自足。不同于其他P450酶,其中P450单加氧酶和电子转移辅助因子蛋白是单独的实体,CYP102A1具有与二黄素电子转移还原酶结构域融合的血红素单加氧酶结构域,其以单个多肽形式含有FAD和FMN辅基两者。CYP102A1的天然底物被认为是线性或支链的中链脂肪酸(参见,例如,Y.,and Fulco,A.J.(1975)Biochim.Biophys.Acta 388,305-317;Cryle,M.J.,et al.,(2006)Chem Commun,2353-2355)。CYP102A1血红素结构域的晶体结构在1993年获得(参见,例如,Ravichandran,K.G.,et al.,(1993)Science 261,731-736),揭示了活性位点结构和底物进入通道的存在。具有结合的底物的晶体结构表明了在底物结合后F87的侧链构象改变(参见,例如,Li,H.,and Poulos,T.L.(1997)Nature Struct.Biol.4,140-146)。
来自巨大芽胞杆菌的CYP102A1是一种自给自足且高效的用于羟基化脂肪酸的酶。已经发现CYP102A1的各种变体可以增强的活性氧化除脂肪酸以外的小分子。然而,尚无用于噻吩并吡啶化合物的杂环缀合物的立体选择性合成的应用。
在开发本发明的实施方式的过程中进行的实验开发了一种以远优于使用肝微粒体的产率产生缀合物的顺式立体异构体的方法。反应涉及将含有BM3变体的细菌胞质级分(0.1-1μM)、2-氧亚基噻吩并吡啶、杂环硫醇和NADPH或NADH混合,然后温育20-60min。在期望杂环硫醇的存在下,该方法以高达100mg每升反应混合物的产率仅产生具有顺式构型的缀合物。
因此,在某些实施方式中,本发明提供了CYP102A1的变体。在一些实施方式中,CYP102A1的变体被优化作为生物催化剂在合成噻吩并吡啶化合物的混合二硫键缀合物的方法中使用。事实上,本文描述的实验通过重新设计CYP102A1的cDNA产生了CYP102A1的优化的基因表达。重新设计的cDNA优化了细菌中过表达的密码子使用,并消除了转录的结构障碍。优化的cDNA在SEQ ID NO:3中示出,并编码1054个氨基酸残基,这些氨基酸残基在N-末端处包括用于亲和纯化的六His标签。在优选的实施方式中,该序列可以在至少20,优选至少30,例如至少40、60、100、200、300、400或更多个连续的氨基酸上,或甚至在同源物的整个序列上,与其具有至少55%、65%、80%或90%,且更优选至少95%、97%或99%的同源性。在一些实施方式中,CYP102A1生物催化剂可以与SEQ ID NO:3具有百分比同一性,该百分比同一性与跨SEQ ID NO:3的任意长度的任何特定百分比同源性值相同(即,其可具有至少40%、55%、80%或90%,且更优选至少95%、97%或99%的同一性)。
同源序列可代表CYP102A1序列的突变部分(SEQ ID NO:3)和/或可以生物催化剂的全长融合多肽的形式存在。
在一些实施方式中,CYP102A1或BM3变体包括与BM3的野生型氨基酸序列(SEQ IDNO:2;图4B)具有85%的同源性的氨基酸序列。在一些实施方式中,BM3变体包括与BM3的野生型氨基酸序列(SEQ ID NO:2;图4B)具有90%的同源性的氨基酸序列。在一些实施方式中,BM3变体包括与BM3的野生型氨基酸序列(SEQ ID NO:2;图4B)具有95%的同源性的氨基酸序列。在一些实施方式中,BM3变体包括与BM3的野生型氨基酸序列(SEQ ID NO:2;图4B)具有99%的同源性的氨基酸序列。在一些实施方式中,BM3变体包括具有在SEQ ID NO:2内的以下氨基酸突变中的一种或多种的氨基酸序列:A82F、L188Q、R47L、F87V、T365N、H116Q、K31T、S56R、A135S、V299D、I458F、P481H和W1046A。在一些实施方式中,BM3变体包括具有表2中所列的一组特定突变的氨基酸序列。
在一些实施方式中,BM3变体包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少85%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少90%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少95%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:1(BM3的野生型cDNA;图4A)具有至少99%的同源性的核酸。
在一些实施方式中,BM3变体包括与SEQ ID NO:3(突变型BM3cDNA;图4C)具有至少85%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少90%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少95%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少99%的同源性的核酸。在一些实施方式中,BM3变体包括与SEQ ID NO:3(突变型BM3 cDNA;图4C)具有至少100%的同源性的核酸。
本文提到的任何同源蛋白(即被描述为与另一蛋白同源)典型地与相关蛋白具有至少为40%的同源性。同源性可以使用已知方法测量。例如,UWGCG软件包提供了BESTFIT程序,其可用于计算同源性(例如按其默认设置使用)(Devereux et al(1984)Nucleic AcidsResearch 12,387-395)。PILEUP和BLAST算法可用于计算同源性或排列序列(典型地按其默认设置),例如,如Altschul S.F.(1993)J Mol Evol 36:290-300;Altschul,S,F et al(1990)J Mol Biol 215:403-10中所述。
本发明的变体CYP102A1酶的生物催化活性或酶活性典型地使用本文提到的任何底物或条件在体外进行测量,并作为NADPH氧化速率、产物形成速率和偶联效率给出。速率为转换频率,并以(nmol NADPH)(nmol CYP102A1)-1(min)-1或(nmol product)(nmolCYP102A1)-1(min)-1给出。偶联效率是用于产物形成所消耗的NADPH的百分比,即理论最大效率的百分比。本发明的CYP102A1酶(例如当用于本发明的合成方法时)典型地可具有至少1%,诸如至少2%、4%、6%、10%、20%、40%、80%或更高的偶联效率。CYP102A1酶(例如当用于本发明的方法时)典型地具有至少2min-1,诸如至少4、10、15、20、25、50、100、200、300、500、700、1000、2000min-1或更高的产物形成速率。在形成多于一种产物的情况下(这是通常的情况),产物形成速率代表所有形成的氧化产物的总量。在一些实施方式中,测量特定氧化产物的产物形成速率,即可以并非测量所有氧化产物。
本文描述的变体CYP102A1生物催化剂(SEQ ID NO:3及其变体;表2中列出的任何突变体)通常通过使用本领域已知的方法引入野生型酶,诸如酶的定点诱变、PCR和基因混编方法,或通过在定点诱变的循环中使用多个诱变寡核苷酸。因此,突变可以直接或随机的方式引入。因此,诱变方法产生编码一种或多种不同突变体的一种或多种多核苷酸。典型地产生突变基因库,其可用于产生突变酶库。
除了在SEQ ID NO:3和表2中指定的一种或多种突变外,该酶还可具有1、2、3、4、5至10,10至20,20至40或更多种其他突变,诸如替换、插入或缺失。这些额外的突变可能会也可能不会增强用于立体选择地且高效地合成噻吩并吡啶化合物的混合二硫键缀合物的方法中的生物催化活性。插入典型地是N和/或C末端。因此,该酶可能含有与末端之一或两端融合的最高达20个氨基酸的短肽或全长蛋白,例如以通过亲和色谱或在固体基质上的固定化来帮助蛋白质纯化。缺失典型地包含与催化无关的氨基酸的缺失,诸如活性位点以外的氨基酸(因此,该酶是天然存在的酶的突变片段)。
当将本发明的变体CYP102A1生物催化剂用于合成噻吩并吡啶化合物的混合二硫键缀合物的方法时,相对于未使用这样的生物催化剂的方法而言,可产生立体选择性的且高效的合成。用于变体CYP102A1生物催化剂催化的氧化过程的底物是任何有机化合物,更典型地,是能够被单加氧酶氧化的任何有机化合物。氧化过程导致形成化合物中的C—O键,通常醇来自碳-氢键的氧化,但环氧化物可能由C═C键的氧化形成。因此,氧化过程可能引入醇、醛、酮或环氧基团。替代地,氧化可能导致含氧基团的进一步氧化,诸如将醇基团转化为醛或酮。同一底物分子中可能有1个、2个或更多个碳原子被攻击。氧化也可导致底物分子的N-和O-脱烷基化。
氧化典型地产生1种、2种或更多种氧化产物。这些不同的产物可能是由于不同碳原子被攻击和/或在给定碳原子上发生不同程度的氧化而产生的。
氧化可以在环碳原子上发生,也可以在取代碳原子上发生,或在两者上都发生。至少初始氧化将涉及攻击可以是活化或非活化的C-H键,或者攻击碳-碳双键(典型地得到环氧化物)。通常,活化的C—H键是在位于苄基或烯丙基位置的碳原子处。芳香环和烯属双键通过稳定反应途径期间生成的自由基中间体或任何电荷累积来活化C-H键进行攻击。C-H键上的碳可以是伯碳、仲碳或叔碳。可能发生氧化导致脱氢使得C═C双键形成而不是插入氧原子。这最可能发生在当烷基取代基是支链的时,或者脱氢导致缀合至芳香系体系的C═C键,或者脱氢导致芳香体系的形成。该过程典型地在变体CYP102A1酶、底物和酶的天然辅助因子(其为NADPH或NADH和双氧)的存在下进行。
在一些实施方式中,变体CYP102A1酶(SEQ ID NO:3及其变体;表2中列出的任何突变体)在细胞内表达。典型地,细胞是其中变体CYP102A1酶(SEQ ID NO:3;表2)或野生型CYP102A1并不天然存在的细胞。在另一实施方式中,变体CYP102A1酶(SEQ ID NO:3;表2)在其中野生型CYP102A1并不天然存在的细胞中表达,但表达水平高于天然存在的水平。该细胞可产生本发明的1、2、3、4种或更多种不同的变体CYP102A1酶。
该细胞可以为原核的或真核的,并且通常为本文所提到的任何细胞或任何生物体。优选的细胞是大肠杆菌(Escherichia coli)、假单胞菌属菌种(Pseudomonas sp.)、黄杆菌(flavobacteria)或真菌细胞(例如,曲霉属(Aspergillus)和酵母,特别是毕赤酵母属菌种(Pichia sp.))。根据本发明还考虑使用红球菌属菌种(Rhodococcus sp.)和芽胞杆菌属菌种(Bacillus sp.)。该细胞可以是也可以不是以其天然存在的形式能够氧化任何底物或生成本文提到的任何氧化产物的细胞。典型地,该细胞是基本分离的形式和/或基本纯化的形式,在这种情况下,它通常包含至少90%,例如至少95%、98%或99%的细胞或制剂的干质量。
典型地,通过将包含编码本发明的变体CYP102A1酶的多核苷酸的载体引入细胞(即用其转化细胞)来产生该细胞。应理解的是,由于核苷酸编码的简并性,多于一种多核苷酸可以编码本发明的每种变体CYP102A1酶。还应理解的是,核苷酸序列可以被设计成表现出适合于特定细胞或生物体的密码子偏好。载体可以整合到细胞的基因组中或保持在染色体外。该细胞可以发育成下文讨论的动物或植物。典型地,多核苷酸的编码序列可操作地连接到控制序列,该控制序列能够提供宿主细胞对编码序列的表达。控制序列通常是启动子,典型地是其中表达单加氧酶的细胞的启动子。
术语“可操作地连接”指的是并置(juxtaposition),其中所描述的组件处于一种允许它们以其预期的方式发挥作用的关系中。将控制序列“可操作地连接”到编码序列上是以这样一种方式进行连接,使得在与控制序列相容的条件下实现编码序列的表达。
载体典型地是转座子、质粒、病毒或噬菌体载体。它典型地包含复制起点。它典型地包含一个或多个可选择的标记基因,例如,在细菌质粒的情况下为氨苄西林抗性基因。典型地使用常规技术,包括磷酸钙沉淀、DEAE-右旋糖酐转染或电穿孔,将载体引入宿主细胞中。
因此,本发明涉及用基因工程生物催化剂高效合成高光学活性的噻吩并吡啶化合物的混合二硫键缀合物的方法,即在存在还原剂(例如NADPH或NADH)以及作为催化剂的所述的细胞色素P450 BM3或CYP102A1的基因工程变体的情况下,通过混合2-氧亚基噻吩并吡啶和杂环硫醇,制备高光学活性的噻吩并吡啶化合物的混合二硫键缀合物的一步法方法。
在某些实施方式中,本发明提供了使用变体CYP102A1(BM3)酶(SEQ ID NO:3;表2)作为生物催化剂用于立体选择性地且高效地合成噻吩并吡啶化合物的混合二硫键缀合物的方法。在一些实施方式中,该方法包括如下反应方案中示出的过程:
如以上反应方案所示,在存在还原剂NADPH或NADH以及作为生物催化剂的变体CYP102A1(BM3)酶(SEQ ID NO:3;表2)的情况下,通过混合反应物2-氧亚基噻吩并吡啶和杂环硫醇来进行合成反应。该反应不需要任何特殊的反应器和设备,也不需要化学合成通常需要的高温和高压。反应在环境温度(例如室温)下在少于60min内完成。
在一些实施方式中,反应涉及将包含BM3变体的细菌胞质级分(0.1-1μM)、2-氧亚基噻吩并吡啶、杂环硫醇和NADPH或NADH混合,然后温育20-60min。在期望杂环硫醇的存在下,该方法以高达100mg每升反应混合物的产率仅产生具有顺式构型的缀合物。
这样的方法导致合成包含噻吩并吡啶化合物的混合二硫键缀合物的基本上对映体纯的组合物和药物组合物。事实上,这样的方法能够以高产率产生所述缀合物的顺式立体异构体形式。
在反应方案中,杂环硫醇并不限于R3的特定化学部分。在一些实施方式中,R3是使得所产生的化合物在与内源性谷胱甘肽(GSH)相互作用时能够产生活性噻吩并吡啶代谢物(例如,具有抗血小板活性的活性噻吩并吡啶代谢物)的任何化学部分。在一些实施方式中,R3是使得所产生的化合物能够治疗、改善或预防患者中的心血管疾患(例如,冠状动脉疾病、周围血管疾病和脑血管疾病)的任何化学部分,诸如对抗血小板剂(诸如,氯吡格雷、噻氯匹定、普拉格雷)有反应的那些疾患。在一些实施方式中,R3是使得所产生的化合物能够通过例如,通过阻断ADP受体改变血小板膜的功能(例如,从而防止允许血小板与纤维蛋白原结合的糖蛋白IIb/IIIa的构像改变)来抑制血小板聚集的任何化学部分。在一些实施方式中,R3是使得所产生的化合物能够通过与P2Y12受体不可逆地结合从而减少血小板的聚集(“凝集”)的任何化学部分。
杂环硫醇部分(R3)的实例包括但不限于表1所示的那些。
表1.用于与2-氧亚基氯吡格雷反应的杂环硫醇的列表
化学名称 | 缩写 |
3-硝基吡啶-2-硫醇 | NPT |
2-巯基吡啶 | MP |
2-巯基-6-甲基吡啶 | MMP |
5-氯吡啶-2-硫醇 | 5-CPT |
2-巯基-5-三氟甲基-吡啶 | 5-TMP |
3-(三氟甲基)吡啶-2-硫醇 | 3-TMP |
2-巯基吡啶-3-甲腈 | MPC |
4,6-二甲基-2-硫代-1,2-二氢吡啶-3-甲腈 | DTDC |
2-喹啉硫醇 | QT |
1-氨基-3-巯基异喹啉 | AMP |
6-氯哒嗪-3-硫醇 | CPT |
2,5-二甲基呋喃-3-硫醇 | DFT |
在一些实施方式中,R3选自
预期用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的这样的方法生成的噻吩并吡啶化合物的混合二硫键缀合物将满足对用于药物开发和生产的缀合物的大规模合成的需要,因为与现有技术方法相比,可预测地以更高的产率生成缀合物的顺式立体异构体。此外,反应是在环境温度和大气压力下进行的,且反应时间短。合成的缀合物容易获得,预期使用本发明的噻吩并吡啶化合物的混合二硫键缀合物作为抗血小板剂将降低毒性,因为毒性反应代谢物不会通过硫醇交换反应产生。此外,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物的治疗起效时间将缩短,这大大有益于经历急性心血管事件的患者。氯吡格雷的标准方案要求持续给药患者3-5天,因为只有一小部分被摄取的氯吡格雷会转化为活性代谢物。与之相比,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物可以在少于30min内以高产率释放活性代谢物。此外,预期本发明的噻吩并吡啶化合物的混合二硫键缀合物将具有相比活性代谢物优越的稳定性,并因此它们可用于定量生成体外基础和临床研究的活性代谢物。
本发明进一步涉及治疗、改善或预防患者中心血管疾患的方法,诸如对抗血小板剂(诸如,氯吡格雷、噻氯匹定和普拉格雷)有反应的那些疾患,该方法包括向患者给药这样的噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)。这样的疾患包括但不限于冠状动脉疾病、外周血管疾病和脑血管疾病。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于抑制血小板聚集,通过例如,通过阻断ADP受体改变血小板膜的功能(例如,从而防止允许血小板与纤维蛋白原结合的糖蛋白IIb/IIIa的构像改变)。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物通过与P2Y12受体不可逆地结合从而减少血小板的聚集(“凝集”)。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于药物组合物中,所述药物组合物配置为用于静脉(IV)给药(例如,在需要IV给药抗血小板剂的医疗情况中(例如,冠状动脉血管成形术))。
在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)用于治疗、改善或预防动物(例如,哺乳动物,包括但不限于人类和兽医动物)中的心血管疾患,诸如对抗血小板剂(诸如,氯吡格雷、噻氯匹定和普拉格雷)有反应的那些疾患,包括向患者给药本发明的噻吩并吡啶化合物的混合二硫键缀合物。这样的疾患包括但不限于冠状动脉疾病、周围血管疾病、动脉粥样硬化血栓形成和脑血管疾病。事实上,在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)用于减少血小板聚集和/或抑制血栓形成。在这方面,使用本发明方法和噻吩并吡啶化合物的混合二硫键缀合物可以治疗或预防这样的疾病和病理。
在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)用于预防有症状性动脉粥样硬化的患者中的血管缺血事件。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于治疗或预防没有ST段抬高的急性冠状动脉综合征。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于预防放置冠状动脉内支架后的血栓形成。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于抑制血小板聚集,通过例如,通过阻断ADP受体改变血小板膜的功能(例如,从而防止允许血小板与纤维蛋白原结合的糖蛋白IIb/IIIa的构像改变)。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物通过与P2Y12受体不可逆地结合从而减少血小板的聚集(“凝集”)。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于延长出血时间。在一些实施方式中,噻吩并吡啶化合物的混合二硫键缀合物用于降低高风险患者中的中风发生率。
在一些实施方式中,本发明提供了配置为用于静脉(IV)给药的包含噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)的药物组合物。在一些实施方式中,这样的配置为用于静脉(IV)给药的包含噻吩并吡啶化合物的混合二硫键缀合物的药物组合物用于治疗、改善和预防动脉粥样硬化血栓形成。在一些实施方式中,这样的配置为用于静脉(IV)给药的包含噻吩并吡啶化合物的混合二硫键缀合物的药物组合物用于快速抑制血小板聚集。在一些实施方式中,这样的配置为用于静脉(IV)给药的包含噻吩并吡啶化合物的混合二硫键缀合物的药物组合物用于在经皮冠状动脉介入手术(例如,冠状动脉血管成形术)中快速抑制血小板聚集。事实上,抗血小板疗法是预防和治疗动脉粥样硬化血栓形成的基础。通过激动剂的血小板活化诸如斑块破裂和来自支架的剪切压力应力在动脉粥样硬化血栓形成的发展中发挥重要作用。在某些患者患有急性心血管综合征或经历经皮心血管介入的临床情况下,需要快速和完全抑制血小板聚集,以防止心血管死亡和缺血性并发症。这样的医疗方案需要静脉给药具有短起效时间的抗血小板剂。然而,这仍然是一个未被满足的医学需求,因为目前使用的抗血小板剂要么起效慢,要么不能静脉给药(参见,例如Silvain,J.,andMontalescot,G.,(2012)Circ.Cariovasc.Interv.5:328-331)。本发明的噻吩并吡啶化合物的混合二硫键缀合物实现了这个未被满足的医学需求,因为这样的化合物既可以口服给药又可以静脉给药,而且具有短起效时间。
本发明的一些实施方式提供了用于给药有效量的本发明的噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)和至少一种额外的治疗剂(包括但不限于已知用于治疗、改善或预防心血管疾患的治疗剂)的方法,和/或治疗技术(例如,外科手术介入)。已知用于治疗、改善或预防心血管疾患的许多治疗剂被设想用于本发明的方法中。事实上,本发明预期但不限于给药已知用于治疗、改善或预防心血管疾患的许多治疗剂。实例包括但不限于HMG-CoA还原酶抑制剂(例如,阿托伐他汀(Lipitor)、普伐他汀(Pravachol)、辛伐他汀(Zocor)、罗素伐他汀(Crestor)、匹伐他汀(Livalo)、洛伐他汀(Mevacor、Altocor)、氟伐他汀(Lescol)、ACE抑制剂(例如,雷米普利(Altace)、喹那普利(Accupril)、卡托普利(Capoten)、依那普利(Vasotec)、赖诺普利(Zestril))、钙通道阻滞剂(例如,氨氯地平(Norvasc)、硝苯地平(Procardia)、维拉帕米(Calan)、非洛地平(Plendil)、地尔硫卓(Cardizem))、血小板聚集抑制剂(除了噻氯匹定、氯吡格雷和普拉格雷之外)(例如,阿昔单抗(ReoPro)、阿司匹林、华法林(香豆素)肝素)、多不饱和脂肪酸(例如,ω-3多不饱和脂肪酸(鱼油))、苯氧酸衍生物(例如,非诺贝特(Tricor)、吉非罗齐(Lopid))、胆汁酸螯合剂(例如,考来替泊(Colestid)、消胆胺(Questran))、抗氧化剂(例如维生素E)、烟酸衍生品(例如,尼克酸(Niaspan)、血栓溶解剂(例如,阿替普酶(Activase))和抗心绞痛剂(例如,雷诺嗪(Ranexa))。
在本发明的一些实施方式中,在以下条件中的一种或多种下,向患者给药本发明的噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)和一种或多种额外的治疗剂:以不同的周期,以不同的持续时间,以不同的浓度,通过不同的给药途径,等等。在一些实施方式中,在额外的治疗剂之前给药噻吩并吡啶化合物的混合二硫键缀合物,例如在给药额外的治疗剂之前0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或者1、2、3或4周。在一些实施方式中,在额外的治疗剂之后给药噻吩并吡啶化合物的混合二硫键缀合物,例如在给药额外的治疗剂之后0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或者1、2、3或4周。在一些实施方式中,同时但以不同的时间表给药噻吩并吡啶化合物的混合二硫键缀合物和额外的治疗剂,例如每天给药噻吩并吡啶化合物的混合二硫键缀合物,同时每周一次、每两周一次、每三周一次或每四周一次给药额外的治疗剂。在其他实施方式中,每周一次给药噻吩并吡啶化合物的混合二硫键缀合物,同时每天、每周一次、每两周一次、每三周一次或每四周一次给药额外的治疗剂。
本发明的范围内的组合物包括其中以有效实现其预期用途的量包含噻吩并吡啶化合物的混合二硫键缀合物(例如,用利用细胞色素P450 BM3或CYP102A1的基因工程变体作为催化剂的方法生成的)的所有组合物。虽然个体的需求各不相同,但确定每种成分的有效量的最佳范围在本领域的技术之内。典型地,可以每天0.0025至50mg/kg哺乳动物体重向哺乳动物(例如人类)口服给药该化合物或等效量的其药学上可接受的盐,所述哺乳动物在接受对诱导细胞凋亡有反应的疾患的治疗。在一种实施方式中,口服给药约0.01至约25mg/kg来治疗、改善或预防此类疾患。对于肌内注射,剂量通常为口服剂量的约一半。例如,合适的肌内注射剂量为约0.0025至约25mg/kg,或约0.01至约5mg/kg。
单位口服剂量可包含约0.01至约1000mg,例如约0.1至约100mg的噻吩并吡啶化合物的混合二硫键缀合物。该单位剂量可以每天一次或多次以一个或多个片剂或胶囊的形式给药,所述片剂或胶囊各自含有约0.1至约10mg,方便地约0.25至50mg的化合物或其溶剂化物。
在局部剂型中,该化合物可以每克载体约0.01至100mg的浓度存在。在一种实施方式中,噻吩并吡啶化合物的混合二硫键缀合物存在的浓度为约0.07-1.0mg/ml,例如约0.1-0.5mg/ml,并且在一种实施方式中为约0.4mg/ml。
除了以原料化学品的形式给药噻吩并吡啶化合物的混合二硫键缀合物之外,本发明的化合物还可以作为含有合适的药学上可接受的载体的药物制剂的一部分给药,所述药学上可接受的载体包含赋形剂和助剂,它们有助于化合物加工成可以在药学上使用的制剂。制剂,特别是那些可以口服或局部给药的制剂以及可用于一种类型的给药的制剂,诸如片剂、糖衣丸、缓释含片和胶囊、口腔冲洗剂和漱口剂、凝胶、液体悬浮液、头发冲洗剂、头发凝胶、洗发剂,以及可以直肠给药的制剂,诸如栓剂,以及用于通过静脉输注、注射、局部或口服给药的合适的溶液,含有约0.01%至99%、在一种实施方式中约0.25%至75%的一种或多种活性化合物,连同赋形剂一起。
本发明的药物组合物可以给药至可能体验到本发明的噻吩并吡啶化合物的混合二硫键缀合物的有益效果的任何患者。这些患者中最首要的是哺乳动物,例如人类,尽管本发明并不旨在局限于此。其他患者包括兽医动物(牛、羊、猪、马、狗、猫等)。
该化合物及其药物组合物可通过达到其预期目的的任何方式给药。例如,给药可通过肠胃外、皮下、静脉内、肌内、腹腔内、经皮、颊部、鞘内、颅内、鼻内或局部途径。替代地,或同时地,可以通过口服途径给药。给药的剂量将取决于接受者的年龄、健康和体重,同时治疗的种类(如果有的话),治疗的频率以及期望效果的性质。
本发明的药物制剂以其本身已知的方式制造,例如通过常规的混合、制粒、制糖衣丸、溶解或冻干工艺。因此,可以通过将活性化合物与固体赋形剂组合,任选地研磨所得到的混合物,并在期望或必要时加入合适的助剂,之后加工颗粒混合物以获得片剂或糖衣丸核,从而获得用于口服用途的药物制剂。
合适的赋形剂,特别是填料,诸如糖类,例如乳糖或蔗糖、甘露醇或山梨醇,纤维素制剂和/或磷酸钙类,例如磷酸三钙或磷酸一氢钙,以及粘结剂,诸如淀粉糊,使用例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如有需要,可以加入崩解剂,诸如上述淀粉类以及羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐,诸如海藻酸钠。助剂首先是流动调节剂和润滑剂,例如二氧化硅、滑石粉、硬脂酸或其盐,诸如硬脂酸镁或硬脂酸钙和/或聚乙二醇。糖衣丸核提供有合适的包衣,如果需要,该包衣可以抵抗胃液。为此目的,可以使用浓缩的糖溶液,其可任选地含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液,以及合适的有机溶剂或溶剂混合物。为了产生抵抗胃液的包衣,使用合适的纤维素制剂的溶液,诸如邻苯二甲酸乙酰基纤维素或邻苯二甲酸羟丙基甲基纤维素。可将染料或颜料加入到片剂或糖衣丸核包衣中,例如用于识别或用于表征活性化合物剂量的组合。
可口服使用的其他药物制剂包括由明胶制成的推入配合(push-fit)胶囊,以及由明胶和增塑剂(诸如甘油或山梨醇)制成的柔软密封胶囊。推合胶囊可含有颗粒形式的活性化合物,其可与填料(诸如乳糖)、粘结剂(诸如淀粉)和/或润滑剂(诸如滑石粉或硬脂酸镁)以及任选地稳定剂混合。在一种实施方式中,在软胶囊中,活性化合物溶解或悬浮于合适的液体中,诸如脂肪油或液体石蜡。此外,可以加入稳定剂。
可直肠使用的可能的药物制剂包括例如栓剂,其由一种或多种活性化合物与栓剂基质的组合组成。合适的栓剂基质是,例如,天然或合成甘油三酯或石蜡烃。此外,还可以使用由活性化合物和基质的组合组成的明胶直肠胶囊。可能的基质材料包括,例如,液体甘油三酯、聚乙二醇或石蜡烃。
用于肠胃外给药的合适的制剂包括水溶性形式的活性化合物的水溶液,例如水溶性盐和碱性溶液。此外,可以将活性化合物的悬浮液作为适当的油性注射悬浮液进行给药。合适的亲脂性溶剂或溶媒包括脂肪油,例如芝麻油,或合成脂肪酸酯,例如油酸乙酯或甘油三酯或聚乙二醇-400。水性注射悬浮液可含有增加悬浮液粘度的物质,包括例如,羧甲基纤维素钠、山梨醇和/或右旋糖酐。任选地,该悬浮液还可含有稳定剂。
在一种实施方式中,本发明的局部组合物通过选择适当的载体配制为油、乳剂、洗剂、软膏等。合适的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量醇(大于C12)。载体可以是活性成分可溶于其中的那些载体。如果需要,还可以包括乳化剂、稳定剂、湿润剂和抗氧化剂以及提供颜色或香味的试剂。此外,经皮渗透增强剂可用于这些局部剂型中。这样的增强剂的实例可以在美国专利号3,989,816和4,444,762中找到。
软膏可以通过将活性成分在植物油(诸如杏仁油)中的溶液与温软的石蜡混合并使混合物冷却来配制。这样的软膏的典型实例是包括按重量计约30%的杏仁油和约70%的白色软石蜡的膏。洗剂可以通过将活性成分溶解在合适的高分子量醇(诸如丙二醇或聚乙二醇)中来方便地制备。
本领域普通技术人员将容易地认识到,上述仅仅代表对本发明的某些优选实施方式的详细描述。上述组合物和方法的各种修改和改变可以使用本技术可用的专业知识容易地获得,并且在本发明的范围内。
实验
实施例I
该实施例描述了噻吩并吡啶化合物的杂环缀合物的立体选择性合成。
以下合成反应方案:
在存在还原剂NADPH或NADH以及作为催化剂的BM3的情况下通过混合反应物2-氧亚基噻吩并吡啶和杂环硫醇来进行。该反应不需要任何特殊的反应器和设备,也不需要化学合成通常需要的高温和高压。在环境温度下,反应在少于60min内完成。测试了一系列杂环硫醇,包括但不限于下表1所示的。
图1示出了氯吡格雷与五种代表性化合物形成混合二硫键缀合物的HPLC分析的结果。后面的“S”表示反应物(±)-2-氧亚基-氯吡格雷的洗脱峰,而星号表示观察到的具有各自硫醇的立体异构体产物。如所预期的,在不存在NADPH的对照样品中,在254nm处仅检测到2-氧亚基氯吡格雷。在NADPH的存在下,观察到以星号标记的产物峰,表明了如上述合成反应方案中所示的产物形成。此前已有报道称,(±)-2-氧亚基-氯吡格雷在非环硫醇的存在下的代谢产生两对产物峰,包括反式和顺式对两者(参见,例如,Zhang,H.,Lauver,D.A.,and Hollenberg,P.F.(2014)Thromb.Haemost.112,1304-1311)。如上述合成反应方案中所示,在谷胱甘肽(GSH)的存在下,在350nm处(在此处2-氧亚基-氯吡格雷不吸收)观察到四个立体异构体。四个立体异构体中的两个与2-氧亚基-氯吡格雷共洗脱。在杂环硫醇的测试集中,只观察到单个或一对产物峰,表明如此前所证明的反应对顺式产物具有立体选择性(参见,例如,Zhang,H.,Lauver,D.A.,and Hollenberg,P.F.(2014)Thromb.Haemost.112,1304-1311)。X射线晶体学的结构分析也证实了顺式构象。在3-TMT和5-TMP的情况下也证实了立体选择性。这两个杂环硫醇除了-CF3基团的位置之外,其他都是相同的。但在3-TMT的存在下,产物量超过在5-TMP的存在下的10倍。
图2示出了氯吡格雷的混合二硫键缀合物的产物的HPLC分析。通过将(±)-2-氧亚基氯吡格雷、杂环硫醇、大鼠LM和NADPH在25℃下混合20min进行反应。
相比之下,对于表1所列的所有测试化合物,在大鼠肝微粒体(LM)中的合成的产率显著低于BM3的情况。例如,在NPT和QT的情况下,在大鼠LM中的产物的量低于图1所示的BM3的情况的十分之一。很明显,BM3中的合成在产率和立体选择性方面优于大鼠LM。定量分析表明,由一升反应混合物可产生~80mg NPT缀合物,如图3所示。
实施例II
该实施例描述了基因工程化BM3突变体以提高合成噻吩并吡啶化合物的混合二硫键缀合物的生产率。
改善细菌细胞中BM3的过表达。
进行实验,通过重新设计BM3的cDNA,优化BM3的基因表达。重新设计的cDNA优化了细菌中过表达的密码子使用,并消除了转录的结构障碍。用于细胞色素P450 BM3或CYP102A1的基因工程变体的优化的cDNA在图4中示出,并编码1054个氨基酸残基,如有需要,则这些氨基酸残基在N-末端处包括六His标签用于亲和纯化。
细菌细胞中BM3的过表达。
在将BM3的cDNA克隆到诸如pCWori、pET28和pLW01的多种载体上之后,进行在包括BL21(DE3)、C41(DE3)、Topp3和DH5α的各种细菌细胞中从构建的质粒过表达BM3的实验。将质粒转化到这些细胞中,并在通过0.6mM异丙基β-D-1-硫代半乳糖苷诱导后,于30℃在氨苄西林的存在下在Terric肉汤培养基中表达16小时。实现了高水平的表达,每升细胞培养物0.5-1g BM3蛋白。对于缀合物的合成,只需要细菌细胞的胞质级分,且不需要通过色谱纯化BM3。
具有增强活性的BM3突变体用于合成噻吩并吡啶类与杂环硫醇的混合二硫键缀合 物。
BM3的天然底物为长链脂肪酸,并因此它对小分子药物几乎没有活性。因此,通过位点定向诱变和直接进化来工程化BM3,以选择用于合成噻吩并吡啶化合物的混合二硫键缀合物的BM3变体。
在筛选BM3突变体的库之后,进行实验,识别表现出合成噻吩并吡啶化合物的混合二硫键缀合物的活性的“s”数量的BM3变体。这些突变体列于表2(野生型氨基酸序列的变体示于图4B)。相对于变体M1的活性归一化活性。这些变体中有7个对合成噻吩并吡啶化合物的混合二硫键缀合物显示出活性,如表3中所示。
表2.具有产生噻吩并吡啶化合物的混合二硫键缀合物的活性的BM3突变体。通过随机诱变或理性设计生成突变体。
BM3突变体 | 突变 |
M1 | A82F |
M2 | A82F/L188Q |
M3 | A82F/L188Q/R47L |
M4 | A82F/L188Q/R47L/F87V |
M5 | A82F/F87V |
M6 | A82F/F87V/R47L |
M7 | A82F/F87V/L188Q |
M8 | A82F/R47L |
M9 | R47L/F87V/L188Q |
M18 | A82F/T365N |
M27 | A82F/F87V/L188Q/H116Q |
M29 | A82F/F87V/L188Q/K31T |
M31 | A82F/F87V/L188Q/S56R/A135S |
M32 | A82F/F87V/L188Q/V299D/I458F/P481H |
M34 | A82F/W1046A |
M35 | A82F/L188Q/R47L/F87V/W1046A |
M36 | A82F/F87V/L188Q/W1046A |
M37 | A82F/F87V/L188Q/W1046L |
M40 | A82F/F87V/L188Q/K31T/W1046A |
表3.在0.25μM BM3的存在下进行反应。
变体 | 产率(mg/L): |
M1 | 18 |
M4 | 9.2 |
M7 | 33.1 |
M9 | 21.4 |
M13 | 14.1 |
M16 | 8.8 |
M37 | 16.7 |
实施例III
该实施例描述了各种形式的CYP102A1的构造、过表达和纯化。
编码全长CYP102A1 A82F突变基因的cDNA序列由Blue Heron Biotechnology(Bothell,WA)合成。然后使用一对NdeI/NotI限制性位点将编码区克隆到pCWori载体上。为便于纯化,在起始密码子ATG后的将六-His标签(6×His标签)序列引入至N-末端,以构建pCW-CYP102A1A82F6×His的质粒。使用pCW-CYP102A1A82F6×His作为模板DNA以及一对引物通过聚合酶链反应(PCR)构建截短的且FLAG标记的CYP102A1。
在0.1mg/mL氨苄西林的存在下,所有形式的CYP102A1构建体在C41(DE3)细胞中均过表达。简言之,将用含有所需基因的pCWori质粒转化的来自C41(DE3)细胞的单个菌落接种到50mL Luria-Bertani(LB)培养基中,并在30℃/180rpm下使培养物生长过夜。使用LB培养基的10mL等分试样接种1L的Terric肉汤(TB)培养基。使TB培养基生长6小时,并通过加入0.6mM异丙基β-D-1-硫代半乳糖苷(IPTG)和0.5mMδ-氨基乙酰丙酸诱导CYP102A1的过表达。诱导后的细胞在30℃下继续生长16hr,并然后通过在2,500g下离心25min而收获。所有蛋白质均用Histrap HP柱(5mL,GE Health Sciences)纯化,如此前所报道的(参见,例如,Zhang,H.,et al.,(2013)Biochemistry 52,355-364)。使用PD-10柱(GE HealthSciences)将纯化后的蛋白质脱盐至0.1M KPi/15%甘油缓冲液(pH 7.4),并以等分试样保存于-80℃下直至使用。
在充分描述了本发明之后,本领域技术人员将理解,在不影响本发明的范围或其任何实施方式的情况下,可以在广泛且等同范围的条件、剂型和其他参数中执行本发明。本文提到的所有专利、专利申请和出版物的全部内容均通过援引整体并入本文。
通过援引并入
本文提到的每份专利文献和科学论文的的完整公开均通过援引并入本文用于所有目的。
等同物
本发明可以在不背离其精神或基本特征的情况下以其他具体形式体现。因此,上述实施方式在所有方面都应被认为是说明性的,而并非限制本文所述的本发明。因此,本发明的范围由所附权利要求书而不是上述说明书指明,并且在权利要求书的等价意义和范围内的所有改变均应包括在其中。
序列表
<110> 密执安大学评议会 (THE REGENTS OF THE UNIVERSITY OF MICHIGAN)
<120> 用于合成噻吩并吡啶化合物的混合二硫键缀合物的生物催化剂和方法
<130> PPI20021368US
<150> US 62/624,494
<151> 2018-01-31
<160> 3
<170> PatentIn version 3.5
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<211> 3150
<212> DNA
<213> 人工序列
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<223> 合成的
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atgacaatta aagaaatgcc tcagccaaaa acgtttggag agcttaaaaa tttaccgtta 60
ttaaacacag ataaaccggt tcaagctttg atgaaaattg cggatgaatt aggagaaatc 120
tttaaattcg aggcgcctgg tcgtgtaacg cgctacttat caagtcagcg tctaattaaa 180
gaagcatgcg atgaatcacg ctttgataaa aacttaagtc aagcgcttaa atttgtacgt 240
gattttgcag gagacgggtt atttacaagc tggacgcatg aaaaaaattg gaaaaaagcg 300
cataatatct tacttccaag cttcagtcag caggcaatga aaggctatca tgcgatgatg 360
gtcgatatcg ccgtgcagct tgttcaaaag tgggagcgtc taaatgcaga tgagcatatt 420
gaagtaccgg aagacatgac acgtttaacg cttgatacaa ttggtctttg cggctttaac 480
tatcgcttta acagctttta ccgagatcag cctcatccat ttattacaag tatggtccgt 540
gcactggatg aagcaatgaa caagctgcag cgagcaaatc cagacgaccc agcttatgat 600
gaaaacaagc gccagtttca agaagatatc aaggtgatga acgacctagt agataaaatt 660
attgcagatc gcaaagcaag cggtgaacaa agcgatgatt tattaacgca tatgctaaac 720
ggaaaagatc cagaaacggg tgagccgctt gatgacgaga acattcgcta tcaaattatt 780
acattcttaa ttgcgggaca cgaaacaaca agtggtcttt tatcatttgc gctgtatttc 840
ttagtgaaaa atccacatgt attacaaaaa gcagcagaag aagcagcacg agttctagta 900
gatcctgttc caagctacaa acaagtcaaa cagcttaaat atgtcggcat ggtcttaaac 960
gaagcgctgc gcttatggcc aactgctcct gcgttttccc tatatgcaaa agaagatacg 1020
gtgcttggag gagaatatcc tttagaaaaa ggcgacgaac taatggttct gattcctcag 1080
cttcaccgtg ataaaacaat ttggggagac gatgtggaag agttccgtcc agagcgtttt 1140
gaaaatccaa gtgcgattcc gcagcatgcg tttaaaccgt ttggaaacgg tcagcgtgcg 1200
tgtatcggtc agcagttcgc tcttcatgaa gcaacgctgg tacttggtat gatgctaaaa 1260
cactttgact ttgaagatca tacaaactac gagctggata ttaaagaaac tttaacgtta 1320
aaacctgaag gctttgtggt aaaagcaaaa tcgaaaaaaa ttccgcttgg cggtattcct 1380
tcacctagca ctgaacagtc tgctaaaaaa gtacgcaaaa aggcagaaaa cgctcataat 1440
acgccgctgc ttgtgctata cggttcaaat atgggaacag ctgaaggaac ggcgcgtgat 1500
ttagcagata ttgcaatgag caaaggattt gcaccgcagg tcgcaacgct tgattcacac 1560
gccggaaatc ttccgcgcga aggagctgta ttaattgtaa cggcgtctta taacggtcat 1620
ccgcctgata acgcaaagca atttgtcgac tggttagacc aagcgtctgc tgatgaagta 1680
aaaggcgttc gctactccgt atttggatgc ggcgataaaa actgggctac tacgtatcaa 1740
aaagtgcctg cttttatcga tgaaacgctt gccgctaaag gggcagaaaa catcgctgac 1800
cgcggtgaag cagatgcaag cgacgacttt gaaggcacat atgaagaatg gcgtgaacat 1860
atgtggagtg acgtagcagc ctactttaac ctcgacattg aaaacagtga agataataaa 1920
tctactcttt cacttcaatt tgtcgacagc gccgcggata tgccgcttgc gaaaatgcac 1980
ggtgcgtttt caacgaacgt cgtagcaagc aaagaacttc aacagccagg cagtgcacga 2040
agcacgcgac atcttgaaat tgaacttcca aaagaagctt cttatcaaga aggagatcat 2100
ttaggtgtta ttcctcgcaa ctatgaagga atagtaaacc gtgtaacagc aaggttcggc 2160
ctagatgcat cacagcaaat ccgtctggaa gcagaagaag aaaaattagc tcatttgcca 2220
ctcgctaaaa cagtatccgt agaagagctt ctgcaatacg tggagcttca agatcctgtt 2280
acgcgcacgc agcttcgcgc aatggctgct aaaacggtct gcccgccgca taaagtagag 2340
cttgaagcct tgcttgaaaa gcaagcctac aaagaacaag tgctggcaaa acgtttaaca 2400
atgcttgaac tgcttgaaaa atacccggcg tgtgaaatga aattcagcga atttatcgcc 2460
cttctgccaa gcatacgccc gcgctattac tcgatttctt catcacctcg tgtcgatgaa 2520
aaacaagcaa gcatcacggt cagcgttgtc tcaggagaag cgtggagcgg atatggagaa 2580
tataaaggaa ttgcgtcgaa ctatcttgcc gagctgcaag aaggagatac gattacgtgc 2640
tttatttcca caccgcagtc agaatttacg ctgccaaaag accctgaaac gccgcttatc 2700
atggtcggac cgggaacagg cgtcgcgccg tttagaggct ttgtgcaggc gcgcaaacag 2760
ctaaaagaac aaggacagtc acttggagaa gcacatttat acttcggctg ccgttcacct 2820
catgaagact atctgtatca agaagagctt gaaaacgccc aaagcgaagg catcattacg 2880
cttcataccg ctttttctcg catgccaaat cagccgaaaa catacgttca gcacgtaatg 2940
gaacaagacg gcaagaaatt gattgaactt cttgatcaag gagcgcactt ctatatttgc 3000
ggagacggaa gccaaatggc acctgccgtt gaagcaacgc ttatgaaaag ctatgctgac 3060
gttcaccaag tgagtgaagc agacgctcgc ttatggctgc agcagctaga agaaaaaggc 3120
cgatacgcaa aagacgtgtg ggctgggtaa 3150
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Pro Leu Leu Val Leu Tyr Gly Ser Asn Met Gly Thr Ala Glu Gly Thr
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Val Ala Thr Leu Asp Ser His Ala Gly Asn Leu Pro Arg Glu Gly Ala
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Lys Met His Gly Ala Phe Ser Thr Asn Val Val Ala Ser Lys Glu Leu
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Gln Gln Pro Gly Ser Ala Arg Ser Thr Arg His Leu Glu Ile Glu Leu
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Arg Asn Tyr Glu Gly Ile Val Asn Arg Val Thr Ala Arg Phe Gly Leu
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Asp Ala Ser Gln Gln Ile Arg Leu Glu Ala Glu Glu Glu Lys Leu Ala
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His Leu Pro Leu Ala Lys Thr Val Ser Val Glu Glu Leu Leu Gln Tyr
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Val Glu Leu Gln Asp Pro Val Thr Arg Thr Gln Leu Arg Ala Met Ala
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Ala Lys Thr Val Cys Pro Pro His Lys Val Glu Leu Glu Ala Leu Leu
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Glu Lys Gln Ala Tyr Lys Glu Gln Val Leu Ala Lys Arg Leu Thr Met
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Leu Glu Leu Leu Glu Lys Tyr Pro Ala Cys Glu Met Lys Phe Ser Glu
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Phe Ile Ala Leu Leu Pro Ser Ile Arg Pro Arg Tyr Tyr Ser Ile Ser
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Ser Asn Tyr Leu Ala Glu Leu Gln Glu Gly Asp Thr Ile Thr Cys Phe
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Ile Ser Thr Pro Gln Ser Glu Phe Thr Leu Pro Lys Asp Pro Glu Thr
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Pro Leu Ile Met Val Gly Pro Gly Thr Gly Val Ala Pro Phe Arg Gly
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Phe Val Gln Ala Arg Lys Gln Leu Lys Glu Gln Gly Gln Ser Leu Gly
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Glu Ala His Leu Tyr Phe Gly Cys Arg Ser Pro His Glu Asp Tyr Leu
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Tyr Gln Glu Glu Leu Glu Asn Ala Gln Ser Glu Gly Ile Ile Thr Leu
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His Thr Ala Phe Ser Arg Met Pro Asn Gln Pro Lys Thr Tyr Val Gln
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Val Glu Ala Thr Leu Met Lys Ser Tyr Ala Asp Val His Gln Val
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<223> 合成的
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atgcaccatc atcatcatca tattaaggag atgccgcagc caaaaacatt cggcgaactc 60
aaaaacttac cattactgaa taccgacaaa ccggtccaag cactgatgaa aattgcggac 120
gaattaggtg aaatcttcaa attcgaggcg cccggtcgcg taacacgtta tttatccagt 180
cagcgcctta tcaaagaagc gtgtgatgaa agtcgttttg ataaaaatct gtcccaggca 240
cttaaatttg ttcgtgactt tttcggtgat ggcctgttta cctcttggac tcatgaaaaa 300
aactggaaaa aagcgcataa tatcttgctt ccgtcgtttt cgcagcaggc aatgaaaggt 360
taccatgcca tgatggtcga tattgccgtc cagctggtgc aaaaatggga acgtcttaac 420
gctgatgaac atattgaagt gcccgaagac atgacccgtc tgacgctgga tactattgga 480
ctgtgcgggt tcaactatcg tttcaactcc ttctaccgtg atcagccaca tccgtttatt 540
acttctatgg tccgcgcctt agacgaagcc atgaacaaac tgcagcgcgc caacccagac 600
gacccagctt atgatgagaa taaacgtcag tttcaagaag acatcaaagt catgaacgac 660
ttagtggata aaattattgc agaccgtaaa gcgagcggcg aacagagtga tgacctgctt 720
acccacatgc tgaatggtaa agatccagag accggcgagc cgttagatga tgaaaatatt 780
cgctaccaga tcattacctt tttaatcgca ggacacgaaa caacaagtgg actgctcagc 840
tttgcactct actttctggt taaaaacccg catgttctgc aaaaagcagc ggaagaggcc 900
gcccgtgtgc tggtcgatcc ggttcccagc tataaacagg tcaaacagtt aaaatacgtg 960
ggcatggtct taaacgaggc tctgcgctta tggccaacag caccagcatt ttcgttatat 1020
gcaaaagaag ataccgttct gggaggagaa tacccgttag aaaaaggcga cgagcttatg 1080
gtgctgatcc cacagttaca ccgtgataaa accatttggg gcgacgatgt ggaagaattt 1140
cgcccagaac gtttcgagaa ccctagcgca attccacagc atgccttcaa acccttcggg 1200
aacggtcagc gcgcgtgcat tgggcagcag ttcgcgctgc atgaagcaac tttggtgtta 1260
ggcatgatgc tgaaacactt tgattttgaa gaccacacga attatgaact ggatattaaa 1320
gaaaccctga cactgaaacc agaaggattc gtagttaaag cgaaaagcaa aaagattccg 1380
ctgggtggca ttccgagccc atccaccgaa cagagcgcga aaaaagttcg gaaaaaggcg 1440
gaaaatgcgc acaatacccc cttgttagtc ctttacggct caaatatggg cacagcagaa 1500
ggcaccgcac gtgacttagc cgatattgca atgagcaagg gtttcgcgcc ccaagtcgcg 1560
accttggatt cacacgctgg aaacctgccg cgggaaggcg ccgtccttat cgttactgcc 1620
tcatataacg gtcaccctcc ggacaatgcg aaacaatttg tggactggtt agatcaagcc 1680
tcggccgacg aagtgaaagg cgttcgttat tctgtttttg gatgtgggga taaaaactgg 1740
gcgacgacgt accaaaaagt ccctgctttt attgatgaaa cgttggctgc aaaaggtgca 1800
gaaaacattg cagaccgtgg cgaagcagac gcgagcgacg actttgaagg tacctatgag 1860
gaatggcgtg aacacatgtg gagtgatgtc gccgcttact tcaacttaga tattgaaaat 1920
tccgaagata ataaaagtac cctgagcttg caattcgtgg actcggctgc cgacatgccg 1980
ctcgctaaaa tgcacggggc gtttagtacg aatgtagtgg cttccaaaga gttgcaacaa 2040
cccggtagcg cacgctcgac ccggcacctg gaaattgaat taccgaagga agcgtcttat 2100
caggaaggag atcatctggg tgtaatccca cgcaattacg aaggtattgt taatcgcgtt 2160
accgcgcgtt ttggtttaga tgcctcccaa caaatccgtt tagaagcaga agaagaaaaa 2220
ctcgcgcatt tacccttagc caaaaccgtt tcggtcgaag aactgctgca atatgttgaa 2280
cttcaggacc ctgtgacccg tacccagctc cgtgccatgg ccgcgaaaac agtatgccca 2340
ccccacaaag ttgaattaga ggcgctgtta gagaaacaag catacaaaga acaagtgtta 2400
gctaagcgtc tgaccatgtt agagttactg gagaaatatc cggcgtgcga gatgaaattc 2460
tcagaattca ttgcattgtt gccgagcatt cgtccgcggt attacagtat ctcgagctca 2520
ccgcgcgttg atgaaaaaca ggcctctatt acggtctccg tagtttccgg cgaagcctgg 2580
agcgggtatg gagaatataa aggaattgct agcaactatc tcgcggagct gcaagagggc 2640
gacactatta catgcttcat ttctacgccg caatccgaat ttacactgcc gaaagacccg 2700
gaaacgccac tcattatggt aggcccaggt actggcgtag cgccatttcg cggattcgtt 2760
caggctcgta aacagttgaa agaacaaggt caaagtcttg gcgaagcaca tttatacttc 2820
ggctgccgct cgccgcatga ggactatctc tatcaggaag aattggagaa cgcacagagt 2880
gagggcatta tcaccttgca tacggctttt tctcgcatgc ctaatcaacc taaaacctat 2940
gtccaacatg tgatggagca ggatggaaaa aaattgatcg agctgttgga tcagggcgcg 3000
catttttaca tttgcgggga tggttcgcag atggcacccg ccgtggaggc cacccttatg 3060
aaaagctatg cagatgtgca ccaggtaagc gaagcggatg cccgtctgtg gctgcaacag 3120
ttggaagaaa aaggtcgcta tgcaaaagac gtgtgggcag gt 3162
Claims (31)
1.一种突变型CYP102A1酶,能够在还原剂的存在下催化2-氧亚基噻吩并吡啶和杂环硫醇之间的缀合。
2.根据权利要求1所述的突变型CYP102A1酶,其中,所述在还原剂的存在下催化2-氧亚基噻吩并吡啶和杂环硫醇之间的缀合导致生成噻吩并吡啶化合物的混合二硫键缀合物。
3.根据权利要求1所述的突变型CYP102A1酶,其中,所述在还原剂的存在下催化2-氧亚基噻吩并吡啶和杂环硫醇之间的缀合选择性地生成了噻吩并吡啶化合物的混合二硫键缀合物的顺式立体异构体。
4.根据权利要求1所述的突变型CYP102A1酶,其中,所述还原剂是NADPH或NADH。
5.根据权利要求1所述的突变型CYP102A1酶,其中,所述酶包括在SEQ ID NO:2内的以下氨基酸突变中的一种或多种:A82F、L188Q、R47L、F87V、T365N、H116Q、K31T、S56R、A135S、V299D、I458F、P481H和W1046A。
6.根据权利要求1所述的突变型CYP102A1酶,其中,所述酶包括具有表2中所列的一组特定突变的氨基酸序列。
7.根据权利要求1所述的突变型CYP102A1酶,其中,所述酶包括与SEQID NO:1具有至少99%的同源性的核酸。
8.根据权利要求1所述的突变型CYP102A1酶,其中,所述酶包括与SEQID NO:3具有至少100%的同源性的核酸。
9.一种用于合成噻吩并吡啶化合物的混合二硫键缀合物的顺式立体异构体的方法,包括在还原剂的存在下混合2-氧亚基噻吩并吡啶部分、杂环硫醇部分和权利要求1所述的突变型CYP102A1酶。
10.根据权利要求9所述的方法,其中,所述还原剂是NADPH或NADH。
12.根据权利要求9所述的方法,其中,所述杂环硫醇部分由R3-SH表示;其中R3选自3-硝基吡啶-2-硫醇、2-巯基吡啶、2-巯基-6-甲基吡啶、5-氯吡啶-2-硫醇、2-巯基-5-三氟甲基-吡啶、3-(三氟甲基)吡啶-2-硫醇、2-巯基吡啶-3-甲腈、4,6-二甲基-2-硫代-1,2-二氢吡啶-3-甲腈、2-喹啉硫醇、1-氨基-3-巯基异喹啉、6-氯哒嗪-3-硫醇和2,5-二甲基呋喃-3-硫醇。
13.根据权利要求9所述的方法,其中,所述混合发生在环境温度下。
14.根据权利要求9所述的方法,其中,所述混合发生的时间段在20至60分钟之间。
15.根据权利要求9所述的方法,其中,所述突变型CYP102A1酶包含在细菌胞质级分中。
16.根据权利要求9所述的方法,其中,所述突变型CYP102A1酶的量在大约0.1至1μM之间。
17.根据权利要求9所述的方法,其中,所述混合导致每升的所述2-氧亚基噻吩并吡啶部分、所述杂环硫醇部分、所述突变型CYP102A1酶和所述还原剂生成大约100mg的噻吩并吡啶化合物的混合二硫键缀合物的顺式立体异构体。
18.一种试剂盒,包含2-氧亚基噻吩并吡啶部分、杂环硫醇部分和权利要求1所述的突变型CYP102A1酶。
19.根据权利要求18所述的试剂盒,还包含还原剂。
20.根据权利要求19所述的试剂盒,其中,所述还原剂是NADPH或NADH。
22.根据权利要求18所述的方法,其中,所述杂环硫醇部分由R3-SH表示;其中R3选自3-硝基吡啶-2-硫醇、2-巯基吡啶、2-巯基-6-甲基吡啶、5-氯吡啶-2-硫醇、2-巯基-5-三氟甲基-吡啶、3-(三氟甲基)吡啶-2-硫醇、2-巯基吡啶-3-甲腈、4,6-二甲基-2-硫代-1,2-二氢吡啶-3-甲腈、2-喹啉硫醇、1-氨基-3-巯基异喹啉、6-氯哒嗪-3-硫醇和2,5-二甲基呋喃-3-硫醇。
23.一种药物组合物,包含用权利要求9所述的方法生成的化合物和药学上可接受的载体。
24.根据权利要求23所述的药物组合物,其中,所述药物组合物配置为用于静脉内给药。
25.一种治疗、改善或预防患者中的心血管疾病的方法,包括向所述患者给药治疗有效量的用权利要求9所述的方法生成的化合物。
26.根据权利要求25所述的方法,其中,所述给药选自由口服给药和静脉内给药组成的组。
27.根据权利要求25所述的方法,其中,所述心血管疾病选自由冠状动脉疾病、周围血管疾病、动脉粥样硬化血栓形成和脑血管疾病组成的组。
28.根据权利要求25所述的方法,其中,所述化合物减少血小板的聚集。
29.根据权利要求28所述的方法,其中,所述减少所述血小板的聚集通过与P2Y12受体不可逆结合而发生。
30.根据权利要求28所述的方法,其中,所述减少所述血小板的聚集通过阻断ADP受体而发生。
31.根据权利要求25所述的方法,还包括共同给药选自由以下组成的组的至少一种剂:HMG-CoA还原酶抑制剂、ACE抑制剂、钙通道阻滞剂、血小板聚集抑制剂、多不饱和脂肪酸、苯氧酸衍生物、胆汁酸螯合剂、抗氧化剂、血栓溶解剂和抗心绞痛剂。
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