Please wait a minute...

中国生物工程杂志

China Biotechnology
China Biotechnology  2010, Vol. 30 Issue (04): 101-109    DOI:
    
Site-specific PEGylation Strategies and Suitable Modified Sites of Protein Drugs
WANG Xu-dong1,LI Xiao-hui1,SU Zhi-guo2,XIU Zhi-long1
1.School of Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China.
2.State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
Download: HTML   PDF(963KB) HTML
Export: BibTeX | EndNote (RIS)      

Abstract  

PEGylation, the covalent attachment of polyethylene glycol (PEG) to proteins, has been used as an effective strategy to overcome several shortcomings of proteins for therapeutic uses. The therapeutic efficacy of PEGylated protein drugs can be improved through prolonging their circulating half-life, reducing their immunogenicity and proteolysis, and increasing their stability and solubility. Furthermore, site-specific PEGylation is an attractive approach for the maximizing the bioavailability of drugs, because a homogeneously modified product with high activity retention and yield can be achieved. Recent advances in site-specific PEGylation were reviewed. The site-specific PEGylation strategies and suitable modified sites were particularly introduced. Finally, the future trends and prospects in site-specific PEGylation were discussed.



Key wordsSite-specificPEGylation      Solid phase PEGylation      Positional isomer      Molecular simulation     
Received: 30 December 2009      Published: 29 April 2010
Cite this article:

WANG Xu-Dong, LI Xiao-Hui, SU Zhi-Guo, XIU Zhi-Long. Site-specific PEGylation Strategies and Suitable Modified Sites of Protein Drugs. China Biotechnology, 2010, 30(04): 101-109.

URL:

https://manu60.magtech.com.cn/biotech/     OR     https://manu60.magtech.com.cn/biotech/Y2010/V30/I04/101

[1] Harris J M, Chess R B. Effect of pegylation on pharmaceuticals. Nature Reviews Drug Discovery, 2003, 2:214221. 
[2] Walsh G. Biopharmaceutical benchmarks. Nature Biotechnology, 2000, 18: 831833. 
[3] Ryan S M, Mantovani G, Wang X, et al. Advances in PEGylation of important biotech molecules: delivery aspects. Expert Opinion Drug Delivery, 2008, 5(4):371383. 
[4] Veronese F M, Pasut G. PEGylation, successful approach to drug delivery. Drug Discovery Today, 2005, 10(21):14511458. 
[5] Fishburn C S. The pharmacology of PEGylation: Balancing PD with PK to generate novel therapeutics. Journal of Pharmaceutical Sciences, 2008, 97(10): 41674183. 
[6]Veronese F M, Pasut G. PEGylation: Posttranslational bioengineering of protein biotherapeutics. Drug Discovery Today: Technologies, 2008, 5(23):e57e64. 
[7] 王凤山, 赵婷, 袁勤生. 蛋白质和多肽的PEG定点修饰研究进展. 2008年中国药学会学术年会暨第八届中国药师周论文集, 2008:23212332. 
[8] 付正明,王洪权,丁建新,等. 蛋白质多肽药物聚乙二醇定点修饰的研究进展. 军事医学科学院院刊, 2007,31(2):178182. Fu Z M, Wang H Q, Ding J X, et al. Bulletin of the Academy of Military Medical Sciences, 2007,31(2):178182. 
[9] 董惠钧,姜俊云,郑立军,等. 蛋白药物聚乙二醇修饰技术研究进展. 中国生化药物杂志,2009,30 (3 ):199203. Dong H J, Jiang J Y, Zheng L J, et al. Chinese Journal of Biochemical Pharmaceutics,2009,30 (3 ):199203. 
[10] Veronese F M, Pasut G. Polymerdrug conjugation, recent achievements and general strategies. Progress in Polymer Science, 2007, 32: 933961. 
[11] Yoshioka Y, Tsutsumi Y, Ikemizu S, et al. Optimal sitespecific PEGylation of mutant TNFa improves its antitumor potency. Biochemical and Biophysical Research Communications, 2004, 315: 808814. 
[12] Youn Y S, Kwon M J, Na D H, et al. Improved intrapulmonary delivery of sitespecific PEGylated salmon calcitonin: Optimization by PEG size selection. Journal of Controlled Release, 2008, 125:6875. 
[13] Fee C J. Sizeexclusion reaction chromatography (SERC): A new technique for protein PEGylation. Biotechnology and Bioengineering, 2003, 82(2): 200206. 
[14] Baran E T, Ozer N, Hasirci V. Solidphase enzyme modification via affinity chromatography. Journal of Chromatography B, 2003, 794:311322. 
[15] Lee B K, Kwon J S, Kim H J, et al. Solidphase PEGylation of recombinant interferon alpha2a for sitespecific modification: process performance, characterization, and in vitro bioactivity. Bioconjugate Chemistry, 2007, 18(6):17281734. 
[16] Suo X Y, Lu X L, Hu T, et al. A solidphase adsorption method for PEGylation of human serum albumin and staphylokinase: preparation, purification and biochemical characterization. Biotechnology Letters, 2009, 31:11911196. 
[17] Suo X Y, Zheng C Y, Yu PZ, et al. Solid phase pegylation of hemoglobin. Artificial Cells, Blood Substitutes, and Biotechnology, 2009, 12:19. 
[18] Hou B B, Li S R, Li X H, et al. Design, preparation and in vitro bioactivity of monopegylated recombinant hirudin. Chinese Journal of Chemical Engineering,2007,15(6):775780. 
[19] 修志龙,李雪芹,李晓晖.一种利用阴离子交换柱辅助聚乙二醇修饰水蛭素的方法:中国专利,200810011554.6, 20081008. Xiu Z L, Li X Q, Li X H. Chinese Patent, 200810011554.6, 20081008. 
[20] Lu Y A, Felix A M. Pegylated peptides II: Solidphase synthesis of amino, carboxy and sidechain pegylated peptides. International Journal of Peptide & Protein Research.,1994, 43(2):127138. 
[21] Kinstler O, Molineux G, Treuheit M, et al. MonoNterminal poly (ethylene glycol)–protein conjugates. Advanced Drug Delivery Reviews, 2002, 54: 477485. 
[22] Youn Y S, Na D H, Lee K C. Highyield production of biologically active monoPEGylated salmon calcitonin by sitespecific PEGylation. Journal of Controlled Release, 2007, 117: 371379. 
[23] Youn Y S, Lee K C. Sitespecific PEGylation for highyield preparation of Lys21amine PEGylated growth hormonereleasing factor (GRF) (129) using a GRF(129) derivative FMOCprotected at Tyr1 and Lys12. Bioconjugate Chemistry, 2007, 18:500506. 
[24] Youn Y S, Chae S Y, Lee S, et al. Evaluation of therapeutic potentials of sitespecific PEGylated glucagonlike peptide1 isomers as a type 2 antidiabetic treatment, insulinotropic activity, glucosestabilizing capability, and proteolytic stability. Biochemical Pharmacolocy, 2007, 73:8493. 
[25] Chae S Y, Chun Y G, Lee S, et al. Pharmacokinetic and pharmacodynamic evaluation of sitespecific PEGylated glucagonlike peptide1 analogs as flexible postprandialglucose controllers. Journal of Pharmaceutical Sciences, 2009, 98(4): 15561567. 
[26] Balan S, Choi J W, Godwin A, et al. Sitespecific PEGylation of protein disulfide bonds using a threecarbon bridge. Bioconjugate Chemistry, 2007, 18:6176. 
[27] Balan S, Brocchini S, Godwin A, et al. Disulfide bridge based PEGylation of proteins. Advanced Drug Delivery Reviews, 2008, 60(1):312. 
[28] 李智华,胡满仓,阎玲梅,等. 人白细胞介素11的定点聚乙二醇修饰. 中国生物工程杂志,2009,29(6):2024. Li Z H, Hu M C, Yan L M, et al. China Biotechnology, 2009,29(6):2024. 
[29] Chi Y S, Zhang H B, Huang W L, et al. Microwaveassisted solid phase synthesis, PEGylation, and biological activity studies of glucagonlike peptide1(7–36) amide. Bioorganic & Medicinal Chemistry, 2008, 16:76077614. 
[30] Fontana A, Spolaore B, Mero A, et al. Sitespecific modification and PEGylation of pharmaceutical proteins mediated by transglutaminase. Advanced Drug Delivery Reviews, 2008, 60: 1328. 
[31] Mero A, Spolaore B, Veronese F M, et al. Transglutaminasemediated PEGylation of proteins: direct identification of the sites of protein modificationby mass spectrometry using a novel monodisperse PEG. Bioconjugate Chemistry, 2009, 20 (2):384389. 
[32] Foser S, Schacher A, Weyer K A, et al. Isolation, structural characterization, and antiviral activity of positional isomers of monopegylated interferon α2a (PEGASYS). Protein Expression and Purification, 2003, 30:7887. 
[33] Lee K C, Moon S C, Park M O, et al. Isolation, characterization, and stability of positional isomers of monoPEGylated salmon calcitonins. Pharmaceutical Research, 1999, 16:813818. 
[34] Esposito P, Barbero L, Caccia P, et al. PEGylation of growth hormonereleasing hormone (GRF) analogues. Advanced Drug Delivery Reviews, 2003, 55:12791291. 
[35] Youn Y S, Na D H, Yoo S D, et al. Chromatographic separation and mass spectrometric identification of positional isomers of polyethylene glycolmodified growth hormonereleasing factor (129). Journal of Chromatography A, 2004, 1061:4549. 
[36]Na D H, Park E J, Jo Y W, et al. Capillary electrophoretic separation of highmolecularweight poly(ethylene glycol)modified proteins. Analytical Biochemistry, 2008, 373(2):207212. 
[37] Veronese F M, Sacca B, Polverino de Laureto P, et al. New PEGs for peptide and protein modification, suitable for identification of the PEGylation site. Bioconjugate Chemistry, 2001, 12(1): 6270. 
[38] Dhalluin C, Ross A, Huber W, et al. Structural, kinetic, and thermodynamic analysis of the binding of the 40 kDa PEGInterferonα2a and its individual positional isomers to the extracellular domain of the receptor IFNAR2. Bioconjugate Chemistry, 2005, 16 (3):518527. 
[39] 胡远东,白坚石,焦克芳,等. PEG修饰牛血红蛋白的计算机模拟研究. 生物物理学 报,2000,16(2 ):315321. Hu Y D, Bai J S, Jiao K F, et al. Acta Biophysica Sinica,2000,16(2 ):315321. 
[40] 赵军,李雪芹,修志龙. PEG在线定点修饰水蛭素及其修饰位点的理论预测与分析. 高等学校化学学报,2009,30(7): 14101416. Zhao J, Li X Q, Xiu Z L. Chemical Journal of Chinese Universities,2009,30(7): 14101416. 
[41] Digilio G, Barbero L, Bracco C, et al. NMR structure of two novel polyethylene glycol conjugates of the human growth hormonereleasing factor, hGRF(129)NH2. Journal of the American Chemical Society, 2003, 125 (12):34583470. 
[42] Svergun D I, Ekstrom F, Vandergriff K D, et al. Solution structure of poly(ethylene) glycolconjugated hemoglobin revealed by smallangle Xray scattering: implications for a new oxygen therapeutic. Biophysical Journal, 2008, 94: 173181. 
[43] Dhalluin C, Ross A, Leuthold L A, et al. Structural and biophysical characterization of the 40 kDa PEGInterferonα2a and its individual positional isomers. Bioconjugate Chemistry, 2005, 16 (3):504517. 
[44] Zloh M, Shaunak S, Balan S, et al. Identification and insertion of 3carbon bridges in protein disulfide bonds: a computational approach. Nature Protocols, 2007, 2:10701083.

No related articles found!