ACE抑制肽的微波合成、活性及分子对接研究
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摘要
血管紧张素Ⅰ转换酶(ACE)在血压调节中起着重要的作用,它可以促进血管紧张素Ⅱ的形成和舒缓激肽的降解,引起血压升高。目前ACE抑制剂已成为临床上治疗高血压的重要药物。
Leu-Arg-Pro(LRP)和Leu-Lys-Pro(LKP)分别是玉米蛋白和鱼蛋白的水解产物,对ACE的抑制活性(IC50)达到了0.27μmol/L和0.32μmol/L。本文以探讨ACE抑制肽的构效关系,设计合成出高活性的ACE抑制肽为目的,针对多肽中氨基酸的组成及分子构象的改变对活性的影响开展工作。以LRP和LKP为骨架,以ACE抑制肽的结构特点为基础,设计合成了包括LRP和LKP在内的16个ACE抑制肽,研究了它们的ACE抑制活性与结构的关系,并通过分子对接分析抑制剂与酶的结合位点。
本文采用微波辅助固相肽合成法,以2-氯三苯甲基氯树脂或Wang树脂为固相载体,运用正交保护策略,Fmoc为N-端α-氨基保护基,HBTU-HOBt为缩合试剂,20%哌啶／DMF为脱保护试剂,合成了LRP和LKP及其类似物共16个序列,粗产物经乙醚沉淀离心,通过RP-HPLC和ESI-MS进行表征。
我们对合成的序列进行了体外ACE抑制活性的测定,结果表明在新设计的14个序列中,Leu-Arg-Pro-Phe-Phe表现出最强的ACE抑制活性,其IC50达到了0.26μmol/L,序列中间Pro的出现可以抵抗体内蛋白酶的水解作用。对于以LRP为骨架的系列,当C-端含有两个相同的氨基酸残基(-Phe-Phe)时,序列具有最高的抑制活性,改变其中的任意一个氨基酸都会导致活性降低；对于以LKP为骨架的系列,当C-端为L-Pro时序列具有最高的抑制活性,其次依次为D-Pro, Ac6c,由此推断ACE对其抑制剂C-端氨基酸残基有很强的立体特异性。
本文采用分子对接对抑制剂与ACE的结合与作用方式进行了研究,结果表明除了序列12和14,其余合成的抑制肽主要占据ACE的S1点,并与Tyr523,Ala356和Glu403等形成氢键,与Phe391和Val518等形成疏水作用以稳定其构象。我们选取活性最好和最差的序列进行了详细的对接分析,其氢键的形成情况也与实验结果一致。
AngiotensinⅠ-converting enzyme(ACE) plays a pivotal role in the regulation of blood pressure. It increases blood pressure by promoting the generation of angiotensin II and the degradation of bradykinin. So angiotensinⅠ-converting enzyme inhibitors are very important drugs for clinical treatment of hypertension.
The tripetpides Leu-Arg-Pro(LRP, isolated from a-zein) and Leu-Lys-Pro (LKP, isolated from fish protein) have IC50 values of 0.27μmol/Land 0.32μmol/L, respectively. In this paper, in order to investigate the structure-activity relationship of ACE inhibitory peptides and design high activity ACE inhibitory peptides, our work focused on the influence of amino acid composition and molecular conformation changes on ACE inhibitory activity. Based on the structures of LRP and LKP, we designed and synthesized 14 new ACE peptide inhibitors, and studied the relationship between ACE inhibitory activity and structure, the binding site between inhibitors and ACE have been analysed by molecular docking.
In this paper, microwave-assisted solid phase peptide synthesis method and Fmoc orthogonal protected strategy were used with Trt(2-Cl) resin or Wang resin as solid carrier、HBTU-HOBt as coupling reagents and 20%piperidine in DMF as deprotecting reagents. LRP、LKP and their analogues have been synthesized. The peptides were then precipitated by ice ether. After centrifugation, the purity and mass of each end-product was analyzed by RP-HPLC and ESI-MS, respectively.
ACE inhibitory activity in vitro was assayed. The result showed that among the 14 new ACE peptides, Leu-Arg-Pro-Phe-Phe showed the strongest inhibition against ACE with an IC50 value of 0.26μmol/L in vitro. The presence of Pro in the middle of the peptide made it very resistant to hydrolysis by digestive enzymes in vivo. For the first series based on LRP, we could see that two identical residues (-Phe-Phe) at the C-terminus yielded the most inhibition, and changing one of the two Phe residues to other amino acid caused a reduction in the inhibitory activity toward ACE; for the second series based on LKP, pepides having L-Pro at the C-termini displayed the highest inhibitory activities, secondly it was D-Pro, and the weakest was Ac6c. ACE therefore appeared to show high stereospecificity with respect to the amino acid residues at the C-termini of these peptide inhibitors.
Molecular docking was performed with the designed peptides as well as the two model peptides (Leu-Arg-Pro and Leu-Arg-Pro), in order to study the binding interaction. The result showed that except peptides 12 and 14, the rest of the synthetic peptides mainly occupied the S1 subsite, forming H-bonds with residues such as Tyr523, Ala356 and Glu403, and also accommodated other interactions with residues such as His353, Phe391 and Val518. The sequences which had the highest and the lowest ACE-inhibitory activities were chose to analyze in details, and the formation of H-bonding was consistent with the result obtained for in vitro activity assay.
Leu-Arg-Pro(LRP)和Leu-Lys-Pro(LKP)分别是玉米蛋白和鱼蛋白的水解产物,对ACE的抑制活性(IC50)达到了0.27μmol/L和0.32μmol/L。本文以探讨ACE抑制肽的构效关系,设计合成出高活性的ACE抑制肽为目的,针对多肽中氨基酸的组成及分子构象的改变对活性的影响开展工作。以LRP和LKP为骨架,以ACE抑制肽的结构特点为基础,设计合成了包括LRP和LKP在内的16个ACE抑制肽,研究了它们的ACE抑制活性与结构的关系,并通过分子对接分析抑制剂与酶的结合位点。
本文采用微波辅助固相肽合成法,以2-氯三苯甲基氯树脂或Wang树脂为固相载体,运用正交保护策略,Fmoc为N-端α-氨基保护基,HBTU-HOBt为缩合试剂,20%哌啶／DMF为脱保护试剂,合成了LRP和LKP及其类似物共16个序列,粗产物经乙醚沉淀离心,通过RP-HPLC和ESI-MS进行表征。
我们对合成的序列进行了体外ACE抑制活性的测定,结果表明在新设计的14个序列中,Leu-Arg-Pro-Phe-Phe表现出最强的ACE抑制活性,其IC50达到了0.26μmol/L,序列中间Pro的出现可以抵抗体内蛋白酶的水解作用。对于以LRP为骨架的系列,当C-端含有两个相同的氨基酸残基(-Phe-Phe)时,序列具有最高的抑制活性,改变其中的任意一个氨基酸都会导致活性降低；对于以LKP为骨架的系列,当C-端为L-Pro时序列具有最高的抑制活性,其次依次为D-Pro, Ac6c,由此推断ACE对其抑制剂C-端氨基酸残基有很强的立体特异性。
本文采用分子对接对抑制剂与ACE的结合与作用方式进行了研究,结果表明除了序列12和14,其余合成的抑制肽主要占据ACE的S1点,并与Tyr523,Ala356和Glu403等形成氢键,与Phe391和Val518等形成疏水作用以稳定其构象。我们选取活性最好和最差的序列进行了详细的对接分析,其氢键的形成情况也与实验结果一致。
AngiotensinⅠ-converting enzyme(ACE) plays a pivotal role in the regulation of blood pressure. It increases blood pressure by promoting the generation of angiotensin II and the degradation of bradykinin. So angiotensinⅠ-converting enzyme inhibitors are very important drugs for clinical treatment of hypertension.
The tripetpides Leu-Arg-Pro(LRP, isolated from a-zein) and Leu-Lys-Pro (LKP, isolated from fish protein) have IC50 values of 0.27μmol/Land 0.32μmol/L, respectively. In this paper, in order to investigate the structure-activity relationship of ACE inhibitory peptides and design high activity ACE inhibitory peptides, our work focused on the influence of amino acid composition and molecular conformation changes on ACE inhibitory activity. Based on the structures of LRP and LKP, we designed and synthesized 14 new ACE peptide inhibitors, and studied the relationship between ACE inhibitory activity and structure, the binding site between inhibitors and ACE have been analysed by molecular docking.
In this paper, microwave-assisted solid phase peptide synthesis method and Fmoc orthogonal protected strategy were used with Trt(2-Cl) resin or Wang resin as solid carrier、HBTU-HOBt as coupling reagents and 20%piperidine in DMF as deprotecting reagents. LRP、LKP and their analogues have been synthesized. The peptides were then precipitated by ice ether. After centrifugation, the purity and mass of each end-product was analyzed by RP-HPLC and ESI-MS, respectively.
ACE inhibitory activity in vitro was assayed. The result showed that among the 14 new ACE peptides, Leu-Arg-Pro-Phe-Phe showed the strongest inhibition against ACE with an IC50 value of 0.26μmol/L in vitro. The presence of Pro in the middle of the peptide made it very resistant to hydrolysis by digestive enzymes in vivo. For the first series based on LRP, we could see that two identical residues (-Phe-Phe) at the C-terminus yielded the most inhibition, and changing one of the two Phe residues to other amino acid caused a reduction in the inhibitory activity toward ACE; for the second series based on LKP, pepides having L-Pro at the C-termini displayed the highest inhibitory activities, secondly it was D-Pro, and the weakest was Ac6c. ACE therefore appeared to show high stereospecificity with respect to the amino acid residues at the C-termini of these peptide inhibitors.
Molecular docking was performed with the designed peptides as well as the two model peptides (Leu-Arg-Pro and Leu-Arg-Pro), in order to study the binding interaction. The result showed that except peptides 12 and 14, the rest of the synthetic peptides mainly occupied the S1 subsite, forming H-bonds with residues such as Tyr523, Ala356 and Glu403, and also accommodated other interactions with residues such as His353, Phe391 and Val518. The sequences which had the highest and the lowest ACE-inhibitory activities were chose to analyze in details, and the formation of H-bonding was consistent with the result obtained for in vitro activity assay.
引文
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