药学学报, 2020, 55(1): 25-32
引用本文:
何佳彧, 梁菊, 宣茂松, 吴文澜. 提高多肽体内稳定性的有效策略[J]. 药学学报, 2020, 55(1): 25-32.
HE Jia-yu, LIANG Ju, XUAN Mao-song, WU Wen-lan. Effective strategies for improving the stability of peptides in vivo[J]. Acta Pharmaceutica Sinica, 2020, 55(1): 25-32.

提高多肽体内稳定性的有效策略
何佳彧1, 梁菊1, 宣茂松1, 吴文澜2
1. 河南科技大学化工与制药学院, 河南 洛阳 471023;
2. 河南科技大学医学院, 河南 洛阳 471023
摘要:
多肽在基因/药物递送和疾病靶向治疗领域应用广泛,但天然多肽在体内容易被蛋白酶水解,半衰期短。很多研究致力于对多肽结构进行一定程度的改造或修饰,希望能够提高多肽的递送和治疗效果。本文总结了近几年文献报道中关于多肽稳定性的研究报道,根据多肽结构改造方式的不同进行文献分类,介绍了各种结构改造和修饰方法对提高多肽的体内循环稳定性和半衰期的作用,有针对性地分析了影响体内多肽稳定性的相关因素,以期为多肽的进一步体内研究和应用提供数据和理论参考。
关键词:    多肽      稳定性      半衰期      环肽      D-型氨基酸     
Effective strategies for improving the stability of peptides in vivo
HE Jia-yu1, LIANG Ju1, XUAN Mao-song1, WU Wen-lan2
1. Chemical Engineering and Pharmaceutics School, Luoyang 471023, China;
2. Medical School, Henan University of Science and Technology, Luoyang 471023, China
Abstract:
Peptides have been extensively used in the fields of gene/drug delivery and disease targeting therapy. However, natural peptides are sensitive to protease digestion with short circulatory half-lives in vivo. Many studies on structural modifications of peptides have been reported to improve the delivery or therapeutic effect. In this review we focus on the recent literature on peptide stability in accordance with different structural modifications and summarize the methods and influential factors that are involved in the improvement of stability and half-life in vivo. This review will provide the scientific basis and theoretical references for further investigations and applications in vivo.
Key words:    peptide    stability    half-life    cyclic peptide    D-amino acid   
收稿日期: 2019-08-29
DOI: 10.16438/j.0513-4870.2019-0696
基金项目: 国家自然科学青年基金项目(51403055);国家自然科学联合基金项目(U1704150).
通讯作者: 梁菊,Tel:13838467989,E-mail:liangju@haust.edu.cn
Email: liangju@haust.edu.cn
相关功能
PDF(1601KB) Free
打印本文
0
作者相关文章
何佳彧  在本刊中的所有文章
梁菊  在本刊中的所有文章
宣茂松  在本刊中的所有文章
吴文澜  在本刊中的所有文章

参考文献:
[1] Sarkar S, Bhatt N, Ha YS, et al. High in vivo stability of (64)Cu-labeled cross-bridged chelators is a crucial factor in improved tumor imaging of RGD peptide conjugates[J]. J Med Chem, 2018, 61:385-395.
[2] Wei XL, Zhan CY, Shen Q, et al. A D-peptide ligand of nicotine acetylcholine receptors for brain-targeted drug delivery[J]. Angew Chem Int Ed, 2015, 54:3023-3027.
[3] Nischan N, Chakrabarti A, Serwa RA, et al. Stabilization of peptides for intracellular applications by phosphoramidate-linked polyethylene glycol chains[J]. Angew Chem Int Ed, 2013, 52:11920-11924.
[4] Ruttekolk IR, Witsenburg JJ, Glauner H, et al. The intracellular pharmacokinetics of terminally capped peptides[J]. Mol Pharm, 2012, 9:1077-1086.
[5] Gao DM, Liu JF, Wang FS. Advances in research on structural stability of peptide drugs[J]. Chin Med Biotechnol, 2007, 2:380-382.
[6] Bogdanowich-Knipp SJ, Jois DS, Siahaan TJ. The effect of conformation on the solution stability of linear vs. cyclic RGD peptides[J]. J Peptide Res, 1999, 53:523-529.
[7] Chan LY, Zhang VM, Huang YH, et al. Cyclization of the antimicrobial peptide gomesin with native chemical ligation:influences on stability and bioactivity[J]. Chembiochem, 2013, 14:617-624.
[8] Li YL, Wu MH, Chang Q, et al. Stapling strategy enables improvement of antitumor activity and proteolytic stability of host-defense peptide hymenochirin-1B[J]. RSC Adv, 2018, 8:22268-22275.
[9] Chen YQ, Yang CQ, Li T, et al. The interplay of disulfide bonds, alpha-helicity, and hydrophobic interactions leads to ultrahigh proteolytic stability of peptides[J]. Biomacromolecules, 2015, 16:2347-2355.
[10] Kim JW, Kim TD, Hong BS, et al. A serum-stable branched dimeric anti-VEGF peptide blocks tumor growth via anti-angiogenic activity[J]. Exp Mol Med, 2010, 42:514-523.
[11] Tugyi R, Uray K, Ivan D, et al. Partial D-amino acid substitution:improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide[J]. Proc Natl Acad Sci U S A, 2005, 102:413-418.
[12] Zhang MF, Lu WY. Enhanced glioma-targeting and stability of (L)GICP peptide coupled with stabilized peptide (D)A7R[J]. Acta Pharm Sin B, 2018, 8:106-115.
[13] Chen L, Tu ZG, Voloshchuk N, et al. Lytic peptides with improved stability and selectivity designed for cancer treatment[J]. J Pharm Sci, 2012, 101:1508-1517.
[14] Seebach D, Lukaszuk A, Patora-Komisarska K, et al. On the terminal homologation of physiologically active peptides as a means of increasing stability in human serum-neurotensin, opiorphin, B27-KK10 epitope, NPY[J]. Chem Biodiv, 2011, 8:711-739.
[15] Koivunen E, Arap W, Valtanen H, et al. Tumor targeting with a selective gelatinase inhibitor[J]. Nat Biotechnol, 1999, 17:768-774.
[16] Björklund M, Valtanen H, Savilahti H, et al. Use of intein-directed peptide biosynthesis to improve serum stability and bioactivity of a gelatinase inhibitory peptide[J]. Comb Chem High Throughput Screen, 2003, 6:29-35.
[17] Mentlein R, Gallwitz B, Schmidt WE. Dipeptidylpeptidase-IV hydrolyzes gastric-inhibitory polypeptide, glucagon-like peptide-1(7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum[J]. Eur J Biochem, 1993, 214:829-835.
[18] HupeSodmann K, Goke R, Goke B, et al. Endoproteolysis of glucagon-like peptide (GLP)-1(7-36) amide by ectopeptidases in RINm5F cells[J]. Peptides, 1997, 18:625-632.
[19] Han J, Huang X, Sun LD, et al. Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity[J]. Biochem Pharmacol, 2013, 86:297-308.
[20] Deng X, Qiu QQ, Ma K, et al. Aliphatic acid-conjugated antimicrobial peptides-potential agents with anti-tumor, multidrug resistance-reversing activity and enhanced stability[J]. Org Biomol Chem, 2015, 13:7673-7680.
[21] Qiao ZY, Lin YX, Lai WJ, et al. A general strategy for facile synthesis and in situ screening of self-assembled polymer-peptide nanomaterials[J]. Adv Mater, 2016, 28:1859-1867.
[22] Ding YP, Ji TJ, Zhao Y, et al. Improvement of stability and efficacy of C16Y therapeutic peptide via molecular self-assembly into tumor-responsive nanoformulation[J]. Mol Cancer Ther, 2015, 14:2390-2400.
[23] Yang L, Zhang L, Yan L, et al. Stability assessment of a new antithrombotic small peptide, Arg-Gly-Asp-Trp-Arg (RGDWR), and its derivative[J]. Biotechnol Lett, 2017, 39:1183-1190.
[24] Ngambenjawong C, Pun SH. Multivalent polymers displaying M2 macrophage-targeting peptides improve target binding avidity and serum stability[J]. ACS Biomater Sci Eng, 2017, 3:2050-2053.
[25] Tang J, Fu H, Kuang QF, et al. Liposomes co-modified with cholesterol anchored cleavable PEG and octaarginines for tumor targeted drug delivery[J]. J Drug Target, 2014, 22:313-326.
[26] Zhang L, Wang Y, Gao Hl, et al. The construction of cell-penetrating peptide R8 and pH sensitive cleavable polyethylene glycols co-modified liposomes[J]. Acta Pharm Sin B, 2015, 5:760-766.
[27] Cheng DB, Yang PP, Cong Y, et al. One-pot synthesis of pH-responsive hyperbranched polymer-peptide conjugates with enhanced stability and loading efficiency for combined cancer therapy[J]. Polym Chem, 2017, 8:2462-2471.
[28] Wu MJ, Huang T, Wang J, et al. Antilung cancer effect of ergosterol and cisplatin-loaded liposomes modified with cyclic arginine-glycine-aspartic acid and octa-arginine peptides[J]. Medicine, 2018, 97:e11916.
[29] Tian R, Zhu SJ, Zeng Q, et al. An albumin sandwich enhances in vivo circulation and stability of metabolically labile peptides[J]. Bioconjug Chem, 2019, 30:1711-1723.
[30] Osborn BL, Olsen HS, Nardelli B, et al. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys[J]. J Pharmacol Exp Ther, 2002, 303:540-548.
[31] Picha KM, Cunningham MR, Drucker DJ, et al. Protein engineering strategies for sustained glucagon-like peptide-1 receptor-dependent control of glucose homeostasis[J]. Diabetes, 2008, 57:1926-1934.
[32] Glaesner W, Vick AM, Millican R, et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein[J]. Diabetes Metab Res Rev, 2010, 26:287-296.
[33] Qu W, Li Y, Hovgaard L, et al. A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1[J]. Int J Nanomed, 2012, 7:4983-4994.
[34] Zhao LQ, Xu HJ, Li Y, et al. Novel application of hydrophobin in medical science:a drug carrier for improving serum stability[J]. Sci Rep, 2016, 6:9.
[35] Ariza-Sáenz M, Espina M, Calpena A, et al. Design, characterization, and biopharmaceutical behavior of nanoparticles loaded with an HIV-1 fusion inhibitor peptide[J]. Mol Pharm, 2018, 15:5005-5018.
[36] Wang YT, Sun T, Zhang Y, et al. Exenatide loaded PLGA microspheres for long-acting antidiabetic therapy:preparation, characterization, pharmacokinetics and pharmacodynamics[J]. RSC Adv, 2016, 6:37452-37462.
[37] Ngambenjawong C, Gustafson HH, Pineda JM, et al. Serum stability and affinity optimization of an M2 macrophage-targeting peptide (M2pep)[J]. Theranostics, 2016, 6:1403-1414.
[38] Medina OP, Soderlund T, Laakkonen LJ, et al. Binding of novel peptide inhibitors of type IV collagenases to phospholipid membranes and use in liposome targeting to tumor cells in vitro[J]. Cancer Res, 2001, 61:3978-3985.
[39] Haikola M, Hirvonen J, Medina OP, et al. Stability and CMC determinations of amphiphilic (DSPE-PEG(3400)-CTT2) peptide constructs by microtensiometry[J]. J Drug Deliv Sci Technol, 2011, 21:183-188.
[40] De Cuyper M, Lievens S, Flo G, et al. Receptor-mediated biological responses are prolonged using hydrophobized ligands[J]. Biosens Bioelectron, 2004, 20:1157-1164.
[41] Zhan CY, Li C, Wei XL, et al. Toxins and derivatives in molecular pharmaceutics:drug delivery and targeted therapy[J]. Adv Drug Deliv Rev, 2015, 90:101-118.
[42] Ying M, Zhan CY, Wang SL, et al. Liposome-based systemic glioma-targeted drug delivery enabled by All-D peptides[J]. ACS Appl Mater Interf, 2016, 8:29977-29985.
[43] Zheng M, Lu R, Che XC, et al. Tyroservatide therapy for tumor growth, invasion and metastasis of Lewis lung carcinoma and human lung carcinoma A549[J]. Oncology, 2006, 70:418-426.
[44] Huang YT, Zhao L, Fu Z, et al. Therapeutic effects of tyroservatide on metastasis of lung cancer and its mechanism affecting integrin-focal adhesion kinase signal transduction[J]. Drug Des Devel Ther, 2016, 10:649-663.
[45] Ren CH, Gao Y, Liu JJ, et al. Anticancer supramolecular hydrogel of D/L-peptide with enhanced stability and bioactivity[J]. J Biomed Nanotechnol, 2018, 14:1125-1134.
相关文献:
1.刘忞之, 杨燕, 张书香, 唐亮, 王惠敏, 陈成娟, 申竹芳, 程克棣, 孔建强, 王伟.紫花地丁中抗甲型H1N1流感病毒的环肽[J]. 药学学报, 2014,49(6): 905-912
2.王江, 柳红.先导化合物结构优化策略(一)——改变代谢途径提高代谢稳定性[J]. 药学学报, 2013,48(10): 1521-1531
3.王向涛;杨天智;李沙;侯新朴.饱和磷脂脂质体的室温下制备及其性质的研究[J]. 药学学报, 2002,37(12): 976-980
4.杨彬;蔡耘;韩宗进;武力民;张其楷;杨松成.鲑鱼降钙素(sCT)类似物在水溶液中的化学稳定性[J]. 药学学报, 1998,33(8): 610-615