Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Pegylation and Cell Based Bioassay of Human Interferon-α2b Along its Docking Studies and Effect on Plasma Half-Life

Author(s): Syeda Kiran Shahzadi*, Muhammad Abdul Qadir, Nasir Mahmood and Mehboob Ahmed

Volume 27, Issue 3, 2020

Page: [219 - 224] Pages: 6

DOI: 10.2174/0929866526666191014124026

Price: $65

Abstract

Background: Interferon-α2b is FDA approved drug for the treatment of chronic HCV and HBV, melanoma, AIDS-related KS, carcinomas, hairy cell leukemia and chronic myelogenous leukemia. However, administration of interferon-α2b to patients takes place thrice in a week due to short in vivo circulation half-life.

Objective: To extend the circulation half-life of IFN-α2b, it is conjugated with polyethylene glycol (PEG). However, PEGylation may results in reduction of its antiviral and antiproliferative activities but on the other side, it results in prolonged plasma half-life.

Methods: Human interferon-α2b was PEGylated with linear 20kDa methoxypolyethlene glycol (mPEG) Propionaldehyde (IFN-Ald20K), Y-Shaped 40kDa mPEG-Propionaldehyde (IFNAld40K), linear 20-kDa mPEG-Succinimidyl Succinate (IFN-NHS20K), and Y shaped 40kDa mPEG-Succinimidyl Succinate (IFN-NHS40K). Impact of PEG size, shape and PEGylation site was studied to establish their relationship with antiprolifetaive activities and serum retention time of PEGylated IFN-α2b.

Result: RP-HPLC studies showed that larger PEGs (40kDa) increased the hydrodynamic volume and increased the serum retention time while antiproliferative activity in HepG2 cell line was decreased with increase in PEGylated interferon-α2b size. Molecular docking results also dictated the same effect that increase in PEGylated interferon-α2b size results in steric shielding of the receptor-binding site on interferon-α2b. IFN-Ald20K showed highest (45%) biological activity with serum half-life 40 hours while IFN-NHS40K showed least (7%) biological activity with serum halflife 56 hours.

Conclusion: Thus, IFN-Ald40K with 12% residual activity and 62 hours of serum half-life proved to be a potent candidate for anticancer and antiviral effect with enhanced serum retention time.

Keywords: Interferon-α2b, PEGylation, antiproliferative activities, protein expression, molecular docking, gene cloning.

« Previous Next »
Graphical Abstract

[1]
Hoffmann, H-H.; Schneider, W.M.; Rice, C.M. Interferons and viruses: An evolutionary arms race of molecular interactions. Trends Immunol., 2015, 36(3), 124-138.
[http://dx.doi.org/10.1016/j.it.2015.01.004] [PMID: 25704559]
[2]
Pfister, D.; Morbidelli, M. Process for protein PEGylation. J. Control. Release, 2014, 180, 134-149.
[http://dx.doi.org/10.1016/j.jconrel.2014.02.002] [PMID: 24531008]
[3]
George, P.M.; Badiger, R.; Alazawi, W.; Foster, G.R.; Mitchell, J.A. Pharmacology and therapeutic potential of interferons. Pharmacol. Ther., 2012, 135(1), 44-53.
[http://dx.doi.org/10.1016/j.pharmthera.2012.03.006] [PMID: 22484806]
[4]
Alconcel, S.N.; Baas, A.S.; Maynard, H.D. FDA-approved poly (ethylene glycol)–protein conjugate drugs. Polym. Chem., 2011, 2(7), 1442-1448.
[http://dx.doi.org/10.1039/c1py00034a]
[5]
Zitvogel, L.; Galluzzi, L.; Kepp, O.; Smyth, M.J.; Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol., 2015, 15(7), 405-414.
[http://dx.doi.org/10.1038/nri3845] [PMID: 26027717]
[6]
Gibbert, K.; Schlaak, J.F.; Yang, D.; Dittmer, U. IFN-α subtypes: Distinct biological activities in anti-viral therapy. Br. J. Pharmacol., 2013, 168(5), 1048-1058.
[http://dx.doi.org/10.1111/bph.12010] [PMID: 23072338]
[7]
Li, W.; Zhan, P.; De Clercq, E.; Lou, H.; Liu, X. Current drug research on PEGylation with small molecular agents. Prog. Polym. Sci., 2013, 38(3-4), 421-444.
[http://dx.doi.org/10.1016/j.progpolymsci.2012.07.006]
[8]
Carter, P.J. Introduction to current and future protein therapeutics: A protein engineering perspective. Exp. Cell Res., 2011, 317(9), 1261-1269.
[http://dx.doi.org/10.1016/j.yexcr.2011.02.013] [PMID: 21371474]
[9]
Jevševar, S.; Kunstelj, M.; Porekar, V.G. PEGylation of therapeutic proteins. Biotechnol. J., 2010, 5(1), 113-128.
[http://dx.doi.org/10.1002/biot.200900218] [PMID: 20069580]
[10]
Swierczewska, M.; Lee, K.C.; Lee, S. What is the future of PEGy-lated therapies? Expert Opin. Emerg. Drugs, 2015, 20(4), 531-536.
[http://dx.doi.org/10.1517/14728214.2015.1113254]
[11]
Roberts, M.; Bentley, M.; Harris, J. Chemistry for peptide and protein PEGylation. Adv. Drug Deliv. Rev., 2012, 64, 116-127.
[http://dx.doi.org/10.1016/j.addr.2012.09.025] [PMID: 12052709]
[12]
Boulestin, A.; Kamar, N.; Sandres-Sauné, K.; Alric, L.; Vinel, J-P.; Rostaing, L.; Izopet, J. Pegylation of IFN-α and antiviral activity. J. Interferon Cytokine Res., 2006, 26(12), 849-853.
[http://dx.doi.org/10.1089/jir.2006.26.849] [PMID: 17238827]
[13]
Chen, X.; Chen, X.; Chen, W.; Ma, X.; Huang, J.; Chen, R. Extended peginterferon alfa-2a (PEGASYS) therapy in Chinese patients with HBeAg-negative chronic hepatitis B. J. Med. Virol., 2014, 86(10), 1705-1713.
[http://dx.doi.org/10.1002/jmv.24013] [PMID: 24980710]
[14]
Su, Y-C.; Chen, B-M.; Chuang, K-H.; Cheng, T-L.; Roffler, S.R. Sensitive quantification of PEGylated compounds by second-generation anti-poly(ethylene glycol) monoclonal antibodies. Bioconjug. Chem., 2010, 21(7), 1264-1270.
[http://dx.doi.org/10.1021/bc100067t] [PMID: 20536171]
[15]
Turecek, P.L.; Bossard, M.J.; Schoetens, F.; Ivens, I.A. PEGylation of biopharmaceuticals: A review of chemistry and nonclinical safety information of approved drugs. J. Pharm. Sci., 2016, 105(2), 460-475.
[http://dx.doi.org/10.1016/j.xphs.2015.11.015] [PMID: 26869412]
[16]
Nasir, M.; Muhammad, A.; Naeem, R. Cloning expression and mutational analysis of human interferon alpha 2 (IFN α2) genes and isolation of antiviral gene sequences; VDM Verlag Dr. Müller: Saarbrücken, Germany, 2011.

Rights & Permissions Print Cite
Article Metrics
6
© 2024 Bentham Science Publishers | Privacy Policy