CN112259166A - 一种靶向prss3的多肽类抑制剂的设计方法、多肽类抑制剂及其制备方法 - Google Patents
一种靶向prss3的多肽类抑制剂的设计方法、多肽类抑制剂及其制备方法 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及了一种靶向PRSS3的多肽类抑制剂的设计方法、多肽类抑制剂及其制备方法,所述的肿瘤靶向多肽WZ‑2的氨基酸序列为PGPCRLDI。本发明利用PRSS3的3D空间结构进行计算机辅助药物设计得到此肿瘤靶向多肽WZ‑2。所述多肽制备方法采用Fmoc固相合成法,以Fmoc‑Ile‑Wang树脂为原料,HOAt/DIC为偶联剂依次连接氨基酸,切割肽后使用HPLC进行纯化得到终产物。本发明的计算机模拟设计技术获得的多肽,对PRSS3的特异性靶向性强,且采用的合成方法生产成本低,反应操作简单,利用实现工业化生产。
Description
技术领域
本发明医药技术领域,特别涉及一种靶向PRSS3的多肽类抑制剂的设计方法、多肽类抑制剂及其制备方法。
背景技术
PRSS3是胰蛋白酶的非典型亚型,只占总胰蛋白酶活性的3%-10%。研究表明PRSS3在胆管癌、肝细胞肝癌、胰腺癌和乳腺癌等多种肿瘤组织中的表达显著高于癌旁组织。PRSS3主要是通过影响肿瘤细胞的侵袭转移来促进肿瘤进展,如RPSS3通过PAR1介导的ERK通路上调VEGF的表达来影响胰腺癌细胞的转移。目前已有关于PRSS3抑制剂作为靶向治疗肿瘤候选药物的研究,例如Kayode 等开展的使用计算机软件模拟设计PRSS3的小分子抑制剂的研究。但是PRSS3 抑制剂用于肿瘤治疗可能会面临与MMP抑制剂类似的问题,即选择性不好。 PRSS3与丝氨酸蛋白酶家族其他成员结构相似,其小分子抑制剂不可避免的会影响相关蛋白酶活性,从而导致一系列不良反应的发生。因此目前将PRSS3的小分子抑制剂应用于临床肿瘤的治疗存在现实困难。
随着X-单晶衍射技术、计算机系统及部件技术的迅猛发展,计算机辅助药物设计取的了巨大进展。计算机分子模拟软件能够分析受体的蛋白晶体与配体结合区域的结构性质,得到受体与配体间的力场、能量和结合位点等信息。利用计算信息即可进行配体模拟物即药物候选物的设计。
目前已有研究中并没有相同靶向PRSS3多肽类抑制剂的相关报道。多肽类抑制剂与PRSS3结合时特异性亲和力要优于小分子抑制剂,它具有肿瘤特异性、安全性、不易产生耐药性的特点。
发明内容
本发明的目的在于针对目前靶向PRSS3的小分子抑制剂选择性差,较难用于肿瘤治疗的困境,以PRSS3蛋白配体模拟物作为先导物,通过不断与PRSS3 蛋白晶体的3D空间结构的对接结果来指导先导物的结构改造,并提供一种靶向PRSS3的多肽类抑制剂的设计方法、多肽类抑制剂及其制备方法,该方法获得的多肽类抑制剂较小分子抑制剂选择性更好且安全性更高。
本发明采用的技术方案如下:
一种靶向PRSS3的多肽类抑制剂的设计方法,采用如下步骤:
a.通过MOE软件或DS软件,分别定义配体即牛胰蛋白酶抑制剂变体与受体即PRSS3蛋白晶体,然后找出受体与配体之间相互作用的作用位点,同时,获得受体与配体之间相互作用力的类型、能量、氨基酸残基间的距离等信息;
b.多肽类抑制剂的序列设计:依据牛胰蛋白酶抑制剂变体来源的模板肽T(TGPCRADI),设计一系列不同序列的多肽与PRSS3蛋白晶体进行对接;为了能改善模板肽的脂水分布情况,以及与受体的结合情况,突变了模板肽中的N-端序列氨基酸并对序列中Arg和Asp之间的氨基酸进行点突变,替换为Ser,Asn, Tyr,Gly,Leu等氨基酸;
c.使用MOE软件或DS软件进行多肽类抑制剂的结构细化,采用LowMode MD 法对多肽序列进行构象分析,然后再与PRSS3受体进行对接,综合多肽构象优化、分子对接和结合能量分析等设计得到多肽类抑制剂。
其中c中所述的靶向PRSS3的多肽类抑制剂为WZ-2(PGPCRLDI),或插入、突变、缺失1~3个氨基酸的多肽序列或相关衍生物。
本发明所述的多肽类抑制剂代表化合物WZ-2,所示结构如下:
本发明还提供上述多肽类抑制剂WZ-2的制备方法。
一种靶向PRSS3的多肽类抑制剂WZ-2的固相合成方法,其步骤如下:
步骤1、采用Fmoc固相合成策略,按多肽类抑制剂WZ-2氨基酸排列序列,依次将Fmoc-Ile-Wang树脂与Fmoc-Asp(R1)-OH、Fmoc-Leu-OH、 Fmoc-Arg(R2)-OH、Fmoc-Cys(R3)-OH、Fmoc-Pro-OH、Fmoc-Gly-OH、 Fmoc-Pro-OH通过多肽偶联剂HOAt及DIC进行连接;
步骤2、使用95%三氟乙酸水溶液将多肽类抑制剂WZ-2从Fmoc-Ile-Wang 树脂上切割下来,再用甲基叔丁基醚沉淀,经HPLC进行纯化,冻干得到目标产物。
所述步骤1中,Fmoc-Ile-Wang树脂(键合量为0.30mmol/g),多肽偶联剂使用4倍当量的HOAt及DIC,偶联反应温度维持在10~30℃。
所述步骤1中,所述的Fmoc-Asp(R1)-OH、Fmoc-Arg(R2)-OH、 Fmoc-Cys(R3)-OH的R1、R2、R3为H、Trt、tBu、Boc、Pbf、OtBu中的任意一种。
所述步骤2中,裂解反应温度维持在0~20℃,反应1~2h,将反应液加入到冷甲基叔丁基醚中沉淀,离心沉淀得到粗肽;使用HPLC进行纯化,采用C18 制备柱,流动相体积比为0.1%TFA的甲醇溶液:水=1:9~9:1;流速为:10ml/min;检测波长为230nm,洗脱得到多肽WZ-2馏分后,冻干得到产物。
本发明提供的靶向PRSS3的多肽类抑制剂WZ-2的制备在治疗肿瘤中的应用,所述肿瘤包括胆管癌、乳腺癌、卵巢癌、肝癌、宫颈鳞癌、肺腺癌和胰腺癌等。
所述的靶向PRSS3的多肽类抑制剂WZ-2为活性成分的药物制剂包括冻干粉针、注射液、片剂、脂质体、纳米制剂等多种形式。
本发明的优点在于:
1、本发明利用计算机软件辅助设计了一种可以靶向PRSS3的多肽类抑制剂 WZ-2,设计方法简单易操作;2、本发明多肽类抑制剂WZ-2可以特异性识别肿瘤相关受体PRSS3;3、本发明的多肽类抑制剂WZ-2克服了PRSS3小分子抑制剂对丝氨酸蛋白酶家族其他成员选择性差、毒副作用大和易产生耐药性等缺点,该方法制备的目标产物WZ-2纯度较高。
附图说明
图1为本发明多肽WZ-2与PRSS3对接的3D模型图;
图2为本发明多肽WZ-2的质谱图。
具体实施方式
下面结合附图和具体的实施例来对本发明进行阐述。
实施例1PRSS3与其蛋白抑制剂相互作用位点的确定
在PDB数据库中下载PRSS3蛋白晶体结构的PDB格式文件(PDB ID: 3p95.pdb),此X-射线晶体结构是胰蛋白酶(PRSS3)与牛胰蛋白酶抑制剂变体复合体的结晶。使用MOE软件打开此PDB文件,对PRSS3受体蛋白模型进行 protonate 3D处理,再通过蛋白contact分析模块,进行受体与配体相互作用的氨基酸残基分析。牛胰蛋白酶抑制剂变体(配体)的残基与PRSS3(受体)通过氢键以及氢键-离子键相互作用,使得配体能嵌入到受体口袋中,从而发挥抑制 PRSS3活性的作用。氨基酸残基分析结果显示牛胰蛋白酶抑制剂变体的Pro13、Cys14,Arg15,Asp17残基与PRSS3的部分残基相互作用。依据PRSS3与其抑制剂的关键结合位点,确定模板肽T的氨基酸序列为TGPCRADI。
实施例2多肽类抑制剂的设计及对接
依此牛胰蛋白酶抑制剂变体来源的模板肽T(TGPCRADI),设计36条含有8 个氨基酸的多肽序列。设计原理主要基于氨基酸空间位置,多肽脂水分布情况以及与受体结合情况等。由于模板与受体的结合位点中Arg和Asp与Arg193的结合尤为重要,所以对模板肽T的6位氨基酸残基(Ala)进行了点突变。Ala属于体积较小的连接氨基酸,所以点突变的氨基酸位阻不易过大,适宜替换的氨基酸有Ser,Asn,Tyr,Gly,Leu。另外还对序列的末端氨基酸残基进行了替换以实现设计多肽的多样性。最后利用MOE的蛋白-蛋白对接模块,基于力场、能量等的打分函数对PRSS3蛋白-多肽WZ-2对接进行模拟计算,得到S score、RMSD 等数据。考察对接的模拟计算结果以及配体受体相互结合情况,确定多肽WZ-2 为优选靶向PRSS3的多肽类抑制剂。如图1所示,3D模型展示出多肽WZ-2能较好的嵌入到PRSS3的活性口袋。
实施例3Fmoc-Ile-Wang树脂的合成
称取wang树脂(1.00equiv)加入到多肽固相合成管内,加入10ml的DMF 浸泡30min,使树脂充分溶胀,再用5ml的DMF洗涤树脂三次,抽干DMF后加入Fmoc-Ile-OH(4.00equiv)、HOAt(4.00equiv)和DIC(4.00equiv)反应10min后加入DMAP(0.4equiv),将反应管放到水平摇床上反应3h,采用Kaiser 试剂监测反应终点。反应结束后抽干反应液,用10ml的DMF洗涤树脂三次。加入10ml的Ac2O/吡啶(5:1v/v)封尾,反应过夜。用10ml DMF洗涤3次,再用5ml的甲醇收缩树脂,将树脂真空干燥以备使用。
实施例4Fmoc-WZ-2-Wang树脂的合成
将Fmoc-Ile-Wang树脂(3.00g,0.90mmol,1.00equiv,0.30mmol/g)加入到多肽固相合成管内,加入10ml的DMF进行洗涤。加入20%哌啶的DMF溶液进行Fmoc保护基的脱除,分别用DCM和DMF洗涤两遍。再将 Fmoc-Asp(otBu)-OH(1.48g,4.00equiv),HOAt(0.49g,4.00equiv)和DIC(0.56ml, 4.00equiv)加入到50ml茄形反应瓶中,再加入10ml DMF搅拌反应20min后,再将反应液加入到多肽固相合成管内。充分摇匀后,将多肽合成管置于水平摇床上反应2.5h。取少量树脂进行Kaiser检测,树脂不显色。抽干液体,分别用DCM 和DMF洗涤两遍得到产物,完成天冬氨酸的缩合。然后依照上述类似步骤,依次连接Fmoc-Leu-OH(1.27g,4.00equiv)、Fmoc-Arg(Pbf)-OH(2.34g,4.00equiv)、 Fmoc-Cys(Trt)-OH(2.11g,4.00equiv)、Fmoc-Pro-OH(1.21g,4.00equiv)、 Fmoc-Gly-OH(1.07g,4.00equiv)、Fmoc-Pro-OH(1.21g,4.00equiv),采用Kaiser检测判断反应终点,抽干反应液,用DMF洗涤2次得到Fmoc-WZ-2-Wang树脂。
实施例5WZ-2的合成
使用10ml的20%Pip的DMF溶液脱去Fmoc-WZ-2-Wang树脂的Fmoc保护基,甲醇收缩树脂。加入肽切割试剂95%的TFA的水溶液,反应温度为10℃,反应2h。使用耐酸滤纸进行过滤,滤液加到甲基叔丁基醚中,生成白色絮状物沉淀,离心得到粗肽。溶解粗肽,经HPLC纯化,然后冻干,到产物0.337g(收率:43%),进行质谱检测,结果见图2。
本发明中一些常用的缩写具有以下含义:
Fmoc:芴甲氧羰基;
DIC:N,N’—二异丙基碳二亚胺;
HOAt:1-羟基-7-偶氮苯并三氮唑;
Pro:脯氨酸;
Leu:亮氨酸;
Gly:甘氨酸;
Arg:精氨酸;
Ile:异亮氨酸;
Asp:天冬氨酸;
Cys:半胱氨酸;
DMF:N,N-二甲基甲酰胺;
DCM:二氯甲烷;
TFA:三氟乙酸;
Pip:六氢吡啶;
Trt:三苯甲基;
tBu:叔丁基;
Pbf:2,2,4,6,7-五甲基二氢苯并呋喃;
Boc:叔丁氧羰基。
OtBu:氧叔丁基。
序列表
<110> 赤峰市医院
<120> 一种靶向PRSS3的多肽类抑制剂的设计方法、多肽类抑制剂及其制备方法
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Thr Gly Pro Cys Arg Ala Asp Ile
1 5
<210> 2
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Pro Gly Pro Cys Arg Leu Asp Ile
1 5
Claims (8)
1.一种靶向PRSS3的多肽类抑制剂的设计方法,其特征在于,采用如下步骤:
a.通过MOE软件或DS软件,分别定义配体即牛胰蛋白酶抑制剂变体与受体即PRSS3蛋白晶体,然后找出受体与配体之间相互作用的作用位点,同时,获得受体与配体之间相互作用力的类型、能量、氨基酸残基间的距离信息;
b.多肽类抑制剂的序列设计:依据牛胰蛋白酶抑制剂变体来源的模板肽T,设计一系列不同序列的多肽与PRSS3蛋白晶体进行对接;并突变了模板肽中的N-端序列氨基酸并对序列中Arg和Asp之间的氨基酸进行点突变,替换为Ser,Asn,Tyr,Gly,Leu氨基酸;
c.使用MOE软件或DS软件进行多肽类抑制剂的结构细化,采用LowMode MD法对多肽序列进行构象分析,然后再与PRSS3受体进行对接,综合多肽构象优化、分子对接和结合能量分析设计得到多肽类抑制剂WZ-2。
2.一种基于权利要求1所述的靶向PRSS3的多肽类抑制剂的设计方法得到的多肽类抑制剂WZ-2,其特征在于,氨基酸序列为PGPCRLDI,或插入、突变、缺失1~3个氨基酸的多肽序列或相关衍生物。
4.根据权利要求3所述的多肽类抑制剂WZ-2,其特征在于,在治疗肿瘤中的应用,所述肿瘤包括胆管癌、乳腺癌、卵巢癌、肝癌、宫颈鳞癌、肺腺癌和胰腺癌。
5.权利要求4所述的多肽类抑制剂WZ-2在治疗肿瘤中的应用,其特征在于,以多肽类抑制剂WZ-2为活性成分的药物制剂包括冻干粉针、注射液、片剂、脂质体、纳米制剂多种形式。
6.权利要求3的多肽类抑制剂WZ-2的制备方法,其特征在于,包括以下步骤:
1)采用Fmoc固相合成策略,按多肽类抑制剂WZ-2氨基酸排列序列,依次将Fmoc-Ile-Wang树脂与Fmoc-Asp(R1)-OH、Fmoc-Leu-OH、Fmoc-Arg(R2)-OH、Fmoc-Cys(R3)-OH、Fmoc-Pro-OH、Fmoc-Gly-OH、Fmoc-Pro-OH通过多肽偶联剂HOAt及DIC进行连接;
2)使用95%三氟乙酸水溶液将多肽类抑制剂WZ-2从Fmoc-Ile-Wang树脂上切割下来,再用甲基叔丁基醚沉淀,经HPLC进行纯化,冻干得到目标产物。
7.根据权利要求6所述的多肽类抑制剂WZ-2的制备方法,其特征在于:使用Fmoc-Ile-Wang树脂,键合量为0.30mmol/g,多肽偶联剂使用4倍当量的HOAt及DIC,偶联反应温度维持在10~30℃。
8.根据权利要求6所述的制备方法,其特征在于,所述的Fmoc-Asp(R1)-OH、Fmoc-Arg(R2)-OH、Fmoc-Cys(R3)-OH的R1、R2、R3为H、Trt、tBu、Boc、Pbf、OtBu中的任意一种。
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