RGDS前体二肽的合成与RGD脂质体剂型的初步研究
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摘要
构成细胞外基质的各种粘连蛋白都含有一个共同的、保守的RGD序列在粘附中起关键作用。用外源含RGD的肽竞争性抑制肿瘤等对正常组织粘附能力,已成为药物设计的新靶点。因此,合成含有RGD的短肽在方法学及相关技术上,需要有所创新和突破。然而,RGD在体内发挥作用时有诸如半衰期短等不足,解决对策是用脂质体作为液相制备的游离RGD的药物载体,以提高药效。
本研究采用化学法和酶法相结合的技术,合成了含RGD且具有抗血栓的靶向性和抗趋药性等突出特性的四肽RGDS的前体二肽Bz-Arg-Gly-NH_2、Z-Asp-Ser-NH_2。应用工业用碱性蛋白酶Alcalase为催化剂,分别以Bz-Arg-OEt·HCl、Z-Asp-OMe为酰基供体,以Gly-NH_2、Ser-NH_2为亲核试剂,在有机溶剂/水双相体系中合成目标产物。并考察了影响肽合成产率的因素,对有机溶剂种类、含水量、pH值、反应温度、反应时间、低物摩尔比等进行了最适化,建立了最佳反应模型。
另外,还采用传统的液相化学法(NCA法)合成出游离RGD三肽。并进行了RGD脂质体剂型的包封等初步研究。
Many adhesive proteins such as fibronectin, vitronectin, collagens, and osteopontin are present in extracellular matrices (ECM) and in the blood cells, which contain a common characteristic tripeptide sequence Arg-Gly-Asp(RGD) as cell recognition site for adhesion. The RGD motif plays a key role in mediating integrin-matrix interaction and RGD-sequence containing peptides are known to be potent anti-adhesive molecules, as they compete for the integrin-matrix recognition process. Their anti-thrombotic, anti-angiogenic, and anti-metastasis effects and the effect of treating osteoporosis have been largely investigated and showed relevant potential clinical applications.Further extensions of the RGD such as X_1-RGD-X_2 (X_1 = Gly, Asp;X_2 = Ser, Cys, Val, Phe) make these sequences even more efficient adhesion to integrin on cell membrane. Aguzzi and others have recently reported that the RGDS peptide exhibits additional potent anti-chemotactic and pro-apoptotic effects independently from its anti-adhesive action, likely by entering the cells and directly activating caspase 8 and caspase 9, and lately caspase 3, implying unexpected intracellular actions of the RGD-motif.Exogenous RGD-containing peptides and proteins have therapeutic value in pathology, they can bind competitively to target sites, block the adhesive proteins-induced generation of some diseases, and can alleviate some diseases as well. They also have therapeutic value in the recovery from burn after operation. Therefore, the research on synthesis of RGD and its derivatives has become a hot spot.At present, many researchers tried to synthesize RGD and RGD-containing peptides (such as RGDS) by chemical or enzymatic methods as it is not available to isolate RGD or other biologically active peptides from whole tissue directly. As compared to the chemical method, the important
benefits of enzymatic peptide synthesis are: a) the mild conditions of the reaction;b) the high regiospecifity of enzyme allowing the use of minimally protected substrates;c) the reaction being stereospecificity without racemization. So, there is an increasing commercial interest in enzymatic preparation of small bioactive peptides.We attempted to synthesize Arg-Gly-Asp-Ser (RGDS) by fragment condensation. One of the major problems encountered in the enzymatic peptide synthesis in organic media is the solubility of substrates. RGDS tetraptide contains two charged amino acids (Arg and Asp) and two neutral amino acids(Gly and Ser). Because of the low solubility of hydrophilic amino acids in hydrophobic organic solvents, the synthesis of hydrophilic amino acid-containing peptides generally proceeds in a rather low yield.The solubility of a hydrophilic amino acid substrate in hydrophobic organic solvents, however, is usually limited due to their high polar. Therefore hydrophilic organic solvents are suitable as the reaction media for the synthesis of hydrophilic amino acid-containing peptides. Nevertheless, enzymes are often deactivated by "water strip" in the hydrophilic solvent. The appropriate solvents should be selected by the balance of the solubility of substrates and enzymatic activity. Simultaneously, enzyme selection and enzyme stability in hydrophilic organic solvent are the key points and should be considered. With regard to the solubility of substrates in organic solvents, we found that acetonitrile was a good candidate for alcalase-catalyzed synthesis of hydrophilic dipeptide.Some papers have reported that an industrial alkaline protease, Alcalase(Novo product) prepared from submerged formation of a selective strain of Bacillus licheniformis, is very stable (half life > 5 days) in ethanol or 2-methyl-2-propanol and suitable for catalysis of peptide bond formation via a kinetically controlled approach. Therefore,we selected Alcalase to catalyze kinetically controlled synthesis of a precursor dipeptide of RGDS
in organic solvents.In this study, a novel chemical method combining with enzyme method was used to prepare the two precursor dipeptides of RGDS (Bz-Arg-Gly-NH2 & Z-Asp-Ser-Nfk). Firstly, using traditional chemical method to systhesize the nucleophile (Gly- NH2 & Ser-NHa) at large scale with low cost. Secondly, The linkage of the acyl donor (Bz-Arg-OEtHCl & Z-Asp-OMe) and nucleophile was completed by using Alcalase under kinetic control condition in organic solvents. The synthesis reaction conditions were optimized by examining the effects of several factors on the Bz-Arg-Gly-Asp-NF^ yields, including Organic Solvents water content, pH, temperature, and reaction time and concentration of the enzyme and the nucleophile, etc.The results are: ? The optimum conditions of the synthesis of Bz-Arg-Gly-Ntb were established to be pH 10.0, 45 °C, in acetonitrile / Na2CO3-NaHCO3 buffer system (90: 10, V/V), lh with the dipeptide yield of 82.9 %.? The optimum conditions of the synthesis of Z-Asp-Ser-NH2are pH 10.0, 35 °C, in acetonitrile / Na2CO3-NaHCO3 buffer system (85: 15, V/V), 6h with the dipeptide yield of 75.5 %.They both Separation and Purification by Sephadex G-10 column (16x1000 mm). Quantitative analysis of the target dipeptide product was carried out by HPLC and the products of target dipeptide were confirmed by LC- MS.Furthermore, free RGD tripeptide has been synthesized by solution phase synthesis method, aspartic acid, chloroacetyl chloride and CBZ-arginine are as materials to synthesize. This kind of synthetic method does not need amino acid to be protected. The purity of HPLC is 70 %. However, a lot of products will be lost in the course of purification.It's time to improve the purity and optimize the purification method further.RGD tripeptide is relatively short in half-life, and very easy to be cleaned away in the body. The RGD-encapsulated liposomes form was prepared. The study is have in hand.
本研究采用化学法和酶法相结合的技术,合成了含RGD且具有抗血栓的靶向性和抗趋药性等突出特性的四肽RGDS的前体二肽Bz-Arg-Gly-NH_2、Z-Asp-Ser-NH_2。应用工业用碱性蛋白酶Alcalase为催化剂,分别以Bz-Arg-OEt·HCl、Z-Asp-OMe为酰基供体,以Gly-NH_2、Ser-NH_2为亲核试剂,在有机溶剂/水双相体系中合成目标产物。并考察了影响肽合成产率的因素,对有机溶剂种类、含水量、pH值、反应温度、反应时间、低物摩尔比等进行了最适化,建立了最佳反应模型。
另外,还采用传统的液相化学法(NCA法)合成出游离RGD三肽。并进行了RGD脂质体剂型的包封等初步研究。
Many adhesive proteins such as fibronectin, vitronectin, collagens, and osteopontin are present in extracellular matrices (ECM) and in the blood cells, which contain a common characteristic tripeptide sequence Arg-Gly-Asp(RGD) as cell recognition site for adhesion. The RGD motif plays a key role in mediating integrin-matrix interaction and RGD-sequence containing peptides are known to be potent anti-adhesive molecules, as they compete for the integrin-matrix recognition process. Their anti-thrombotic, anti-angiogenic, and anti-metastasis effects and the effect of treating osteoporosis have been largely investigated and showed relevant potential clinical applications.Further extensions of the RGD such as X_1-RGD-X_2 (X_1 = Gly, Asp;X_2 = Ser, Cys, Val, Phe) make these sequences even more efficient adhesion to integrin on cell membrane. Aguzzi and others have recently reported that the RGDS peptide exhibits additional potent anti-chemotactic and pro-apoptotic effects independently from its anti-adhesive action, likely by entering the cells and directly activating caspase 8 and caspase 9, and lately caspase 3, implying unexpected intracellular actions of the RGD-motif.Exogenous RGD-containing peptides and proteins have therapeutic value in pathology, they can bind competitively to target sites, block the adhesive proteins-induced generation of some diseases, and can alleviate some diseases as well. They also have therapeutic value in the recovery from burn after operation. Therefore, the research on synthesis of RGD and its derivatives has become a hot spot.At present, many researchers tried to synthesize RGD and RGD-containing peptides (such as RGDS) by chemical or enzymatic methods as it is not available to isolate RGD or other biologically active peptides from whole tissue directly. As compared to the chemical method, the important
benefits of enzymatic peptide synthesis are: a) the mild conditions of the reaction;b) the high regiospecifity of enzyme allowing the use of minimally protected substrates;c) the reaction being stereospecificity without racemization. So, there is an increasing commercial interest in enzymatic preparation of small bioactive peptides.We attempted to synthesize Arg-Gly-Asp-Ser (RGDS) by fragment condensation. One of the major problems encountered in the enzymatic peptide synthesis in organic media is the solubility of substrates. RGDS tetraptide contains two charged amino acids (Arg and Asp) and two neutral amino acids(Gly and Ser). Because of the low solubility of hydrophilic amino acids in hydrophobic organic solvents, the synthesis of hydrophilic amino acid-containing peptides generally proceeds in a rather low yield.The solubility of a hydrophilic amino acid substrate in hydrophobic organic solvents, however, is usually limited due to their high polar. Therefore hydrophilic organic solvents are suitable as the reaction media for the synthesis of hydrophilic amino acid-containing peptides. Nevertheless, enzymes are often deactivated by "water strip" in the hydrophilic solvent. The appropriate solvents should be selected by the balance of the solubility of substrates and enzymatic activity. Simultaneously, enzyme selection and enzyme stability in hydrophilic organic solvent are the key points and should be considered. With regard to the solubility of substrates in organic solvents, we found that acetonitrile was a good candidate for alcalase-catalyzed synthesis of hydrophilic dipeptide.Some papers have reported that an industrial alkaline protease, Alcalase(Novo product) prepared from submerged formation of a selective strain of Bacillus licheniformis, is very stable (half life > 5 days) in ethanol or 2-methyl-2-propanol and suitable for catalysis of peptide bond formation via a kinetically controlled approach. Therefore,we selected Alcalase to catalyze kinetically controlled synthesis of a precursor dipeptide of RGDS
in organic solvents.In this study, a novel chemical method combining with enzyme method was used to prepare the two precursor dipeptides of RGDS (Bz-Arg-Gly-NH2 & Z-Asp-Ser-Nfk). Firstly, using traditional chemical method to systhesize the nucleophile (Gly- NH2 & Ser-NHa) at large scale with low cost. Secondly, The linkage of the acyl donor (Bz-Arg-OEtHCl & Z-Asp-OMe) and nucleophile was completed by using Alcalase under kinetic control condition in organic solvents. The synthesis reaction conditions were optimized by examining the effects of several factors on the Bz-Arg-Gly-Asp-NF^ yields, including Organic Solvents water content, pH, temperature, and reaction time and concentration of the enzyme and the nucleophile, etc.The results are: ? The optimum conditions of the synthesis of Bz-Arg-Gly-Ntb were established to be pH 10.0, 45 °C, in acetonitrile / Na2CO3-NaHCO3 buffer system (90: 10, V/V), lh with the dipeptide yield of 82.9 %.? The optimum conditions of the synthesis of Z-Asp-Ser-NH2are pH 10.0, 35 °C, in acetonitrile / Na2CO3-NaHCO3 buffer system (85: 15, V/V), 6h with the dipeptide yield of 75.5 %.They both Separation and Purification by Sephadex G-10 column (16x1000 mm). Quantitative analysis of the target dipeptide product was carried out by HPLC and the products of target dipeptide were confirmed by LC- MS.Furthermore, free RGD tripeptide has been synthesized by solution phase synthesis method, aspartic acid, chloroacetyl chloride and CBZ-arginine are as materials to synthesize. This kind of synthetic method does not need amino acid to be protected. The purity of HPLC is 70 %. However, a lot of products will be lost in the course of purification.It's time to improve the purity and optimize the purification method further.RGD tripeptide is relatively short in half-life, and very easy to be cleaned away in the body. The RGD-encapsulated liposomes form was prepared. The study is have in hand.
引文
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