功能性多肽的设计、合成及其应用研究
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摘要
随着多肽合成技术和高效液相纯化、分析等技术的迅速发展,多肽类化合物作为一类重要的生物活性分子,越来越受到研究人员的关注。其中,多肽类物质的生物兼容性、特异性蛋白识别能力、易于修饰、易降解等特点,使其广泛受到药物开发者的青睐,成为药物研究中一个新的活跃领域。近年来,研究人员发现,一些短肽能够通过氢键、静电作用力,疏水作用以及π-π堆积等方式,白组装成各种有序的纳米结构,从而使其在药物的包覆、运输、缓释,生物传感、催化剂以及纳米器件等研究领域产生了广泛应用。基于以上考虑,在本论文中,设计合成了系列功能性多肽,并研究了其作为抗肿瘤靶向药物和神经退行性疾病阻断剂的活性。同时,针对与老年痴呆病理相关的淀粉样蛋白的自组装功能,设计合成了易于自组装成纳米纤维的短肽,并研究了其在催化材料和生物传感方面的应用。本论文的主要内容包括：
(1)通过液相多肽合成法合成了Fc-RGD和Fc-Am-RGD,利用MTT细胞毒性法和流式细胞仪法研究了它们的抗肿瘤活性,并用高效液相色谱-电化学联用法(HPLC-EC)研究了B16细胞对其摄取能力。研究发现,Fc-RGD和Fc-Am-RGD相对于它们的母体RGD和二茂铁具有更强的抗癌活性,且在二茂铁和RGD之间插入柔性片段6-氨基己酸的Fc-Am-RGD表现出了最强的抗肿瘤活性,其IC5o值为5.2±1.4μmol·L-1。另外HPLC-EC的研究结果也证实了Fc-Am-RGD穿透B16细胞膜的能力比Fc-RGD强。
(2)合成了GPR三肽,GPR-Fca和Fc-GPR。通过ThT荧光分析法和原子力显微镜研究了合成物质对Ap聚集的影响,并利用电化学方法研究了其与Ap的相互作用。研究结果表明：Fc-GPR不能抑制Aβ的聚集,而GPR和GPR-Fca则能有效抑制Ap的聚集以及解聚己形成的Ap纤维,而GPR-Fca的抑制聚集和解聚能力都要强于其母体GPR。特别是,GPR-Fca能够显著降低因Ap的聚集而引起的神经细胞毒性。同时,GPR-Fca还表现出了很强的抗酶解能力和较好的亲脂性。
(3) α-syn的聚集和聚集物的神经细胞毒性在帕金森病(PD)的致病机理中扮演中重要的角色。而Cu2+能促进α-syn的聚集以及Cu2+存在下α-syn聚集物神经细胞毒性显著增加的现象更是让人们深信α-syn-Cu2+聚集物在PD中的重要作用。以α-syn的原生序列77VAQKTV82为识别肽设计合成了甲基化的VAQTKmV作为α-syn-Cu2+聚集的阻断剂。通过ThT荧光法和AFM研究了其抑制α-syn-Cu2+聚集的过程,并用MTT法研究了其对α-syn-Cu2+聚集物引起的神经细胞毒性的抑制作用。研究发现,VAQTKmV不仅能有效地抑制α-syn-Cu2+的聚集,而且能显著降低由α-syn-Cu2+的聚集所引起的神经细胞毒性。
(4)细胞内蛋白α-syn的构象变化以及聚集过程被认为与PD的病理学紧密相关,它以α-螺旋结构的形式聚集在突触前末端。通过将无定形的α-syn加入到三氟乙醇和水的混合液中使其转换成α-螺旋结构,利用电化学和紫外光谱的方法研究了Cu+和Cu2+与其结合能力,并发现a-螺旋结构的α-syn与Cu+的结合能力较之与Cu2+的结合能力高两个数量级,比无定形结构α-syn与Cu2+的结合能力则更是高出三个数量级之多。通过对含有游离Cu2+、无定形α-syn-Cu2+以及a-螺旋α-syn-Cu2+的溶液中H202和OH·的检测发现,α-螺旋结构的α-syn对Cu+的高稳定作用能显著降低自由基的产生。
(5)通过固相法合成了能自组装成带正电荷纳米纤维的苯胺-GGAAKLVFF多肽。通过静电作用,将带负电的Pt纳米粒子直接固定到多肽纤维表面。这种Pt纳米粒子负载的多肽纤维在催化氧还原方面具有非常高的催化活性,可能会在燃料电池领域产生潜在的应用价值。
(6)将苯胺连接到自组装型的淀粉样多肽片段GGAAKLVFF的N端,通过多肽固相合成的方法合成了Aniline-GGAAKLVF(AP)。AP不仅能够自组装成多肽纳米纤维,其露在纤维表面的苯胺单体还能够在H2O2和HRP的作用下实现聚合,形成高电化学活性的聚苯胺外壳。因此,结合苯胺在HRP催化下的聚合特性及聚合后聚苯胺良好的电化学信号构建了以自组装多肽纳米纤维为模板的,具有较高灵敏度和选择性的核酸传感器。
Due to the inherent biocompatibility, biodegradability, specific protein recognition ability, easy to modify and purify at laboratory, peptides have been extensively used in the field of drug research and development. More importantly, during the last decade, researchers have demonstrated that some peptides can self-assembly into various well-ordered nanostructures which are attractive to many applications (e.g., drug delivery, biosensor, catalysis, nanodevice and so on). Their ability to form such structures is due to structural complementarities coupled with hydrogen bonding, electrostatic interaction, hydrophobic affinity and π-stacking (aromatic amino acids). Based on the above considerations, we designed and synthesized a series of peptides, and studied their applications in the field of antitumor, anti-neurodegerative disease, catalysis and biosensior.
(1) Ferrocenoyl RGD conjugates Fc-RGD and Fc-Am-RGD (Am:6-aminohexanoic acid) were synthesized, and the antitumor activities in vitro were investigated. The cell uptake of the conjugates by B16murine melanoma cells was measured using HPLC-electrochemical method. The antitumor activities of the conjugates were also evaluated by MTT and flow cytometric measurements. The experimental results revealed that Fc-RGD and Fc-Am-RGD exhibit more effective antitumor activities than their parent compounds RGD and Fc-COOH. Moreover, it is found that Fc-Am-RGD yields the lowest IC50values of5.2±1.4μmol·L-1toward B16cells. The HPLC-electrochemical studies confirmed the insertion of flexible alkyl spacer Am between Fc and RGD significantly increases the cell uptake toward B16cells and consequently improves the antitumor activity. Our results suggest that Fc-RGD and Fc-Am-RGD conjugates are potential candidates for cancer treatment.
(2) The conjugates of ferrocene and Gly-Pro-Arg (GPR) tripeptide, GPR-Fca and Fc-GPR (Fc:ferrocene; Fca:ferrocene amino acid) were synthesized by HOBt/HBTU protocol in solution. These ferrocene GPR conjugates were employed to inhibit Aβ(1-42) fibrillogenesis and to disaggregate preformed A(3fibrils. The inhibitory properties of ferrocene GPR conjugates on Aβ(1-42) fibrillogenesis were evaluated by thioflavin T fluorescence assay, and confirmed by AFM analysis. The interaction between the ferrocene GPR conjugates and Aβ(1-42) was monitored by electrochemical means. Our results showed that both GPR and GPR-Fca can significantly inhibit the fibril formation of Aβ(1-42), and cause disaggregation of the preformed fibrils. As expected, GPR-Fca shows stronger inhibitory effect on Aβ(1-42) fibrillogenesis than that of its parent peptide GPR. In contrast, Fc-GPR shows no inhibitory effect on fibrillogenesis of Aβ(1-42). Furthermore, GPR-Fca demonstrates significantly protection against Aβ-induced cytotoxicity and exhibits high resistance to proteolysis and good lipophilicity.
(3) The aggregation and fibrillation of α-syn have been implicated as a causative factor in Parkinson's disease (PD). α-syn can binds to copper and the aggregation of α-syn is stimulated in the presence of copper attracted great attention. Particularly, recently studies have shown that the toxicity of α-syn aggregates significantly increased in the presence of copper, which make researchers to believe that α-syn-Cu2+aggregates play key role in PD. In this study,N-methylated peptide (VAQKTmV) was synthesized and employed as an inhibitor to prevent the aggregation of a-syn-Cu2+. The inhibitory properties of VAQKTmV on a-syn-Cu2+fibrillation were evaluated by ThT fluorescence assay, and confirmed by AFM analysis. Our results demonstrated that VAQKTmV can not only strongly inhibit the aggregation of α-syn-Cu2+, but also significantly prevent the α-syn-Cu2+-induced cytotoxicity toward SH-SY5Y cells.
(4) In this study, circular dichroism confirmed that natively unstructured α-syn in aqueous solution was transformed to its α-helical conformation upon addition of trifluoroethanol. Electrochemical and UV-visible spectroscopic experiments reveal that both Cu+and Cu2+are stabilized, with the former being stabilized by about two orders of magnitude. Compared to unstructured α-syn, α-helical α-syn stabilizes Cu+by more than three orders of magnitude. Through the measurements of H2O2and hydroxyl radicals (OH·) in solutions containing different forms of Cu2+(free and complexed by unstructured or α-helical α-syn), we demonstrate that the significantly enhanced Cu+binding affinity helps inhibit the production of highly toxic reactive oxygen species, especially the hydroxyl radicals. Our study provides strong evidence that, as a possible means to prevent neuronal cell damage, conversion of the natively unstructured a-syn to its a-helical conformation in vivo could significantly attenuate the copper-modulated ROS production.
(5) Self-assembly peptides, due to their inherent biocompatibility, molecular-recognition capability and functional flexibility, have been recognized as very useful building block for creating nanostructures. In this study, aniline-GGAAKLVFF peptide (AFP) was prepared by solid-phase synthesis. The AFP peptide can readily self-assemble into amyloid-like fibrils in a simple way, then the negatively charged Pt NPs were directly assemble onto the positively charged surface of the fibrils via electrostatic interaction. The Pt-AFP fibrils exhibited excellent electrocatalytic activities toward oxygen reduction, which is of special interest for polymer electrolyte fuel cells, batteries and other electrode applications.
(6) Polyaniline has been of great interest to many researchers due to its excellent electrical properties, is a unique type of conducting polymer. In this study, aniline was conjugated to the N-terminal of amyloid-like peptide GGAAKLVFF by solid-phase synthesis. The aniline-GGAA-KLVFF peptide not only can readily self-assemble into fibrils in a simple way, but also forms polyaniline by the extruding aniline of peptide fibrils in the present of H2O2and HRP. The polyaniline nanowire retains polyaniline full electrochemical activity and was successfully used as signal amplification to fabricate a sensitive nucleic acid detecter.
(1)通过液相多肽合成法合成了Fc-RGD和Fc-Am-RGD,利用MTT细胞毒性法和流式细胞仪法研究了它们的抗肿瘤活性,并用高效液相色谱-电化学联用法(HPLC-EC)研究了B16细胞对其摄取能力。研究发现,Fc-RGD和Fc-Am-RGD相对于它们的母体RGD和二茂铁具有更强的抗癌活性,且在二茂铁和RGD之间插入柔性片段6-氨基己酸的Fc-Am-RGD表现出了最强的抗肿瘤活性,其IC5o值为5.2±1.4μmol·L-1。另外HPLC-EC的研究结果也证实了Fc-Am-RGD穿透B16细胞膜的能力比Fc-RGD强。
(2)合成了GPR三肽,GPR-Fca和Fc-GPR。通过ThT荧光分析法和原子力显微镜研究了合成物质对Ap聚集的影响,并利用电化学方法研究了其与Ap的相互作用。研究结果表明：Fc-GPR不能抑制Aβ的聚集,而GPR和GPR-Fca则能有效抑制Ap的聚集以及解聚己形成的Ap纤维,而GPR-Fca的抑制聚集和解聚能力都要强于其母体GPR。特别是,GPR-Fca能够显著降低因Ap的聚集而引起的神经细胞毒性。同时,GPR-Fca还表现出了很强的抗酶解能力和较好的亲脂性。
(3) α-syn的聚集和聚集物的神经细胞毒性在帕金森病(PD)的致病机理中扮演中重要的角色。而Cu2+能促进α-syn的聚集以及Cu2+存在下α-syn聚集物神经细胞毒性显著增加的现象更是让人们深信α-syn-Cu2+聚集物在PD中的重要作用。以α-syn的原生序列77VAQKTV82为识别肽设计合成了甲基化的VAQTKmV作为α-syn-Cu2+聚集的阻断剂。通过ThT荧光法和AFM研究了其抑制α-syn-Cu2+聚集的过程,并用MTT法研究了其对α-syn-Cu2+聚集物引起的神经细胞毒性的抑制作用。研究发现,VAQTKmV不仅能有效地抑制α-syn-Cu2+的聚集,而且能显著降低由α-syn-Cu2+的聚集所引起的神经细胞毒性。
(4)细胞内蛋白α-syn的构象变化以及聚集过程被认为与PD的病理学紧密相关,它以α-螺旋结构的形式聚集在突触前末端。通过将无定形的α-syn加入到三氟乙醇和水的混合液中使其转换成α-螺旋结构,利用电化学和紫外光谱的方法研究了Cu+和Cu2+与其结合能力,并发现a-螺旋结构的α-syn与Cu+的结合能力较之与Cu2+的结合能力高两个数量级,比无定形结构α-syn与Cu2+的结合能力则更是高出三个数量级之多。通过对含有游离Cu2+、无定形α-syn-Cu2+以及a-螺旋α-syn-Cu2+的溶液中H202和OH·的检测发现,α-螺旋结构的α-syn对Cu+的高稳定作用能显著降低自由基的产生。
(5)通过固相法合成了能自组装成带正电荷纳米纤维的苯胺-GGAAKLVFF多肽。通过静电作用,将带负电的Pt纳米粒子直接固定到多肽纤维表面。这种Pt纳米粒子负载的多肽纤维在催化氧还原方面具有非常高的催化活性,可能会在燃料电池领域产生潜在的应用价值。
(6)将苯胺连接到自组装型的淀粉样多肽片段GGAAKLVFF的N端,通过多肽固相合成的方法合成了Aniline-GGAAKLVF(AP)。AP不仅能够自组装成多肽纳米纤维,其露在纤维表面的苯胺单体还能够在H2O2和HRP的作用下实现聚合,形成高电化学活性的聚苯胺外壳。因此,结合苯胺在HRP催化下的聚合特性及聚合后聚苯胺良好的电化学信号构建了以自组装多肽纳米纤维为模板的,具有较高灵敏度和选择性的核酸传感器。
Due to the inherent biocompatibility, biodegradability, specific protein recognition ability, easy to modify and purify at laboratory, peptides have been extensively used in the field of drug research and development. More importantly, during the last decade, researchers have demonstrated that some peptides can self-assembly into various well-ordered nanostructures which are attractive to many applications (e.g., drug delivery, biosensor, catalysis, nanodevice and so on). Their ability to form such structures is due to structural complementarities coupled with hydrogen bonding, electrostatic interaction, hydrophobic affinity and π-stacking (aromatic amino acids). Based on the above considerations, we designed and synthesized a series of peptides, and studied their applications in the field of antitumor, anti-neurodegerative disease, catalysis and biosensior.
(1) Ferrocenoyl RGD conjugates Fc-RGD and Fc-Am-RGD (Am:6-aminohexanoic acid) were synthesized, and the antitumor activities in vitro were investigated. The cell uptake of the conjugates by B16murine melanoma cells was measured using HPLC-electrochemical method. The antitumor activities of the conjugates were also evaluated by MTT and flow cytometric measurements. The experimental results revealed that Fc-RGD and Fc-Am-RGD exhibit more effective antitumor activities than their parent compounds RGD and Fc-COOH. Moreover, it is found that Fc-Am-RGD yields the lowest IC50values of5.2±1.4μmol·L-1toward B16cells. The HPLC-electrochemical studies confirmed the insertion of flexible alkyl spacer Am between Fc and RGD significantly increases the cell uptake toward B16cells and consequently improves the antitumor activity. Our results suggest that Fc-RGD and Fc-Am-RGD conjugates are potential candidates for cancer treatment.
(2) The conjugates of ferrocene and Gly-Pro-Arg (GPR) tripeptide, GPR-Fca and Fc-GPR (Fc:ferrocene; Fca:ferrocene amino acid) were synthesized by HOBt/HBTU protocol in solution. These ferrocene GPR conjugates were employed to inhibit Aβ(1-42) fibrillogenesis and to disaggregate preformed A(3fibrils. The inhibitory properties of ferrocene GPR conjugates on Aβ(1-42) fibrillogenesis were evaluated by thioflavin T fluorescence assay, and confirmed by AFM analysis. The interaction between the ferrocene GPR conjugates and Aβ(1-42) was monitored by electrochemical means. Our results showed that both GPR and GPR-Fca can significantly inhibit the fibril formation of Aβ(1-42), and cause disaggregation of the preformed fibrils. As expected, GPR-Fca shows stronger inhibitory effect on Aβ(1-42) fibrillogenesis than that of its parent peptide GPR. In contrast, Fc-GPR shows no inhibitory effect on fibrillogenesis of Aβ(1-42). Furthermore, GPR-Fca demonstrates significantly protection against Aβ-induced cytotoxicity and exhibits high resistance to proteolysis and good lipophilicity.
(3) The aggregation and fibrillation of α-syn have been implicated as a causative factor in Parkinson's disease (PD). α-syn can binds to copper and the aggregation of α-syn is stimulated in the presence of copper attracted great attention. Particularly, recently studies have shown that the toxicity of α-syn aggregates significantly increased in the presence of copper, which make researchers to believe that α-syn-Cu2+aggregates play key role in PD. In this study,N-methylated peptide (VAQKTmV) was synthesized and employed as an inhibitor to prevent the aggregation of a-syn-Cu2+. The inhibitory properties of VAQKTmV on a-syn-Cu2+fibrillation were evaluated by ThT fluorescence assay, and confirmed by AFM analysis. Our results demonstrated that VAQKTmV can not only strongly inhibit the aggregation of α-syn-Cu2+, but also significantly prevent the α-syn-Cu2+-induced cytotoxicity toward SH-SY5Y cells.
(4) In this study, circular dichroism confirmed that natively unstructured α-syn in aqueous solution was transformed to its α-helical conformation upon addition of trifluoroethanol. Electrochemical and UV-visible spectroscopic experiments reveal that both Cu+and Cu2+are stabilized, with the former being stabilized by about two orders of magnitude. Compared to unstructured α-syn, α-helical α-syn stabilizes Cu+by more than three orders of magnitude. Through the measurements of H2O2and hydroxyl radicals (OH·) in solutions containing different forms of Cu2+(free and complexed by unstructured or α-helical α-syn), we demonstrate that the significantly enhanced Cu+binding affinity helps inhibit the production of highly toxic reactive oxygen species, especially the hydroxyl radicals. Our study provides strong evidence that, as a possible means to prevent neuronal cell damage, conversion of the natively unstructured a-syn to its a-helical conformation in vivo could significantly attenuate the copper-modulated ROS production.
(5) Self-assembly peptides, due to their inherent biocompatibility, molecular-recognition capability and functional flexibility, have been recognized as very useful building block for creating nanostructures. In this study, aniline-GGAAKLVFF peptide (AFP) was prepared by solid-phase synthesis. The AFP peptide can readily self-assemble into amyloid-like fibrils in a simple way, then the negatively charged Pt NPs were directly assemble onto the positively charged surface of the fibrils via electrostatic interaction. The Pt-AFP fibrils exhibited excellent electrocatalytic activities toward oxygen reduction, which is of special interest for polymer electrolyte fuel cells, batteries and other electrode applications.
(6) Polyaniline has been of great interest to many researchers due to its excellent electrical properties, is a unique type of conducting polymer. In this study, aniline was conjugated to the N-terminal of amyloid-like peptide GGAAKLVFF by solid-phase synthesis. The aniline-GGAA-KLVFF peptide not only can readily self-assemble into fibrils in a simple way, but also forms polyaniline by the extruding aniline of peptide fibrils in the present of H2O2and HRP. The polyaniline nanowire retains polyaniline full electrochemical activity and was successfully used as signal amplification to fabricate a sensitive nucleic acid detecter.
引文
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