Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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

Application of Cell Penetrating Peptides for Intracellular Delivery of Endostatin: A Computational Approach

Author(s): Mozhdeh Zamani*, Navid Nezafat, Pooneh Mokarram and Behnam Kadkhodaei*

Volume 20, Issue 3, 2024

Published on: 15 May, 2023

Page: [208 - 223] Pages: 16

DOI: 10.2174/1573409919666230426093230

Price: $65

conference banner
Abstract

Background: Endostatin is an antiangiogenic compound with anticancer activity. The poor stability and low half-life of endostatin are the main barriers to the clinical use of this protein. Cell-penetrating peptides (CPPs) are extensively applied as carrier in the delivery of drugs and different therapeutic agents. Therefore, they can be proper candidates to improve endostatin delivery to the target cells.

Objective: In this study, we aim to computationally predict appropriate CPPs for the delivery of endostatin.

Methods: Potential appropriate CPPs for protein delivery were selected based on the literature. The main parameters for detection of best CPP-endostatin fusions, including stability, hydrophobicity, antigenicity, and subcellular localization, were predicted using ProtParam, VaxiJen, and DeepLoc-1.0 servers, respectively. The 3D structures of the best CPP-Endostatin fusions were modeled by the I-TASSER server. The predicted models were validated using PROCHECK, ERRAT, Verify3D and ProSA-Web servers. The best models were visualized by the PyMol molecular graphics system.

Results: Considering the principal parameters in the selection of best CPPs for endostatin delivery, endostatin fusions with four CPPs, including Cyt c-ss-MAP, TP-biot1, MPGα, and DPV1047, high stability and hydrophobicity, no antigenicity and extracellular localization were predicted as the best potential fusions for endostatin delivery. Four CPPs, including Cyt c-ss-MAP, TP-biot1, MPGα, and DPV1047, were predicted as the best potential candidates to improve endostatin delivery.

Conclusion: Application of these CPPs may overcome the limitation of endostatin therapeutic applications, including poor stability and low half-life. Subsequent experimental studies will contribute to verifying these computational results.

« Previous Next »
Graphical Abstract

[1]
Habault, J.; Poyet, J.L. Recent advances in cell penetrating peptide-based anticancer therapies. Molecules, 2019, 24(5), 927.
[http://dx.doi.org/10.3390/molecules24050927] [PMID: 30866424]
[2]
Teleanu, R.I.; Chircov, C.; Grumezescu, A.M.; Teleanu, D.M. Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J. Clin. Med., 2019, 9(1), 84.
[http://dx.doi.org/10.3390/jcm9010084] [PMID: 31905724]
[3]
Wu, T.; Duan, X.; Hu, T.; Mu, X.; Jiang, G.; Cui, S. Effect of endostatin on Wnt pathway of stem-like cells in bladder cancer in tumor microenvironment. Mol. Biol. Rep., 2020, 47(5), 3937-3948.
[http://dx.doi.org/10.1007/s11033-020-05487-3] [PMID: 32388699]
[4]
Hua, L.; Ping, L.; Hong-Yan, G. Recent advances on the modified endostatin and ocular neovascularization. Int. J. Ophthalmol., 2009, 2(4), 642-644.
[5]
Mohajeri, A.; Sanaei, S.; Kiafar, F.; Fattahi, A.; Khalili, M.; Zarghami, N. The challenges of recombinant endostatin in clinical application: Focus on the different expression systems and molecular bioengineering. Adv. Pharm. Bull., 2017, 7(1), 21-34.
[http://dx.doi.org/10.15171/apb.2017.004] [PMID: 28507934]
[6]
Poluzzi, C.; Iozzo, R.V.; Schaefer, L. Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers. Adv. Drug Deliv. Rev., 2016, 97, 156-173.
[http://dx.doi.org/10.1016/j.addr.2015.10.012] [PMID: 26518982]
[7]
Ramakrishnan, S.; Bui Nguyen, T.M.; Subramanian, I.V.; Kelekar, A. Autophagy and angiogenesis inhibition. Autophagy, 2007, 3(5), 511-514.
[http://dx.doi.org/10.4161/auto.4734] [PMID: 17643071]
[8]
Nguyen, T.M.B.; Subramanian, I.V.; Xiao, X.; Ghosh, G.; Nguyen, P.; Kelekar, A.; Ramakrishnan, S. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and β-catenin levels. J. Cell. Mol. Med., 2009, 13(9b), 3687-3698.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00722.x] [PMID: 19298526]
[9]
Li, K.; Shi, M.; Qin, S. Current status and study progress of recombinant human endostatin in cancer treatment. Oncol. Ther., 2018, 6(1), 21-43.
[http://dx.doi.org/10.1007/s40487-017-0055-1] [PMID: 32700135]
[10]
Ren, Z.; Wang, Y.; Jiang, W.; Dai, W.; Jiang, Y. Anti-tumor effect of a novel soluble recombinant human endostatin: administered as a single agent or in combination with chemotherapy agents in mouse tumor models. PLoS One, 2014, 9(9), e107823.
[http://dx.doi.org/10.1371/journal.pone.0107823] [PMID: 25229620]
[11]
Wang, Z.Q.; Wang, D.S.; Wang, F.H.; Ren, C.; Tan, Q.; Li, Y.H. Recombinant human endostatin plus paclitaxel/nedaplatin for recurrent or metastatic advanced esophageal squamous cell carcinoma: A prospective, single-arm, open-label, phase II study. Invest. New Drugs, 2021, 39(2), 516-523.
[http://dx.doi.org/10.1007/s10637-020-01021-1] [PMID: 33070249]
[12]
Chen, L.; Shi, H.; Che, Y.; Sun, W.; Niu, X.; Lu, W. Verification of protein structures: Patterns of nonbonded atomic interactions transcatheter arterial infusion and chemoembolization on gastric cancer with liver metastasis and analysis of prognosis. J. BUON, 2020, 25, 1469-1475.
[PMID: 32862592]
[13]
Hai-Tao, Z.; Hui-Cheng, L.; Zheng-Wu, L.; Chang-Hong, G. A tumor-penetrating peptide modification enhances the antitumor activity of endostatin in vivo. Anticancer Drugs, 2011, 22(5), 409-415.
[http://dx.doi.org/10.1097/CAD.0b013e328342050d] [PMID: 21427563]
[14]
Lee, T.Y.; Tjin Tham Sjin, R.M.; Movahedi, S.; Ahmed, B.; Pravda, E.A.; Lo, K.M.; Gillies, S.D.; Folkman, J.; Javaherian, K. Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy. Clin. Cancer Res., 2008, 14(5), 1487-1493.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-1530] [PMID: 18316573]
[15]
Guo, L.; Xu, B.; Zhou, D.; Chang, G.; Fu, Y.; Liu, L.; Luo, Y. Biophysical and biological characterization of PEGylated recombinant human endostatin. Clin. Exp. Pharmacol. Physiol., 2019, 46(10), 920-927.
[http://dx.doi.org/10.1111/1440-1681.13134] [PMID: 31278773]
[16]
Tan, H.; Yang, S.; Feng, Y.; Liu, C.; Cao, J.; Mu, G.; Wang, F. Characterization and secondary structure analysis of endostatin covalently modified by polyethylene glycol and low molecular weight heparin. J. Biochem., 2008, 144(2), 207-213.
[http://dx.doi.org/10.1093/jb/mvn060] [PMID: 18463113]
[17]
Jing, Y.; Lu, H.; Wu, K.; Subramanian, I.V.; Ramakrishnan, S. Inhibition of ovarian cancer by RGD-P125A-endostatin-Fc fusion proteins. Int. J. Cancer, 2011, 129(3), 751-761.
[http://dx.doi.org/10.1002/ijc.25932] [PMID: 21225621]
[18]
Idiiatullina, E.; Al-Azab, M.; Walana, W.; Pavlov, V.; Liu, B. EnDuo, a novel derivative of Endostar, inhibits the migration of colon cancer cells, suppresses matrix metalloproteinase-2/9 expression and impedes AKT/ERK activation. Biomed. Pharmacother., 2021, 134, 111136.
[http://dx.doi.org/10.1016/j.biopha.2020.111136] [PMID: 33341042]
[19]
Lindgren, M.; Hällbrink, M.; Prochiantz, A.; Langel, Ü. Cell-penetrating peptides. Trends Pharmacol. Sci., 2000, 21(3), 99-103.
[http://dx.doi.org/10.1016/S0165-6147(00)01447-4] [PMID: 10689363]
[20]
Milletti, F. Cell-penetrating peptides: Classes, origin, and current landscape. Drug Discov. Today, 2012, 17(15-16), 850-860.
[http://dx.doi.org/10.1016/j.drudis.2012.03.002] [PMID: 22465171]
[21]
Derossi, D.; Joliot, A.H.; Chassaing, G.; Prochiantz, A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem., 1994, 269(14), 10444-10450.
[http://dx.doi.org/10.1016/S0021-9258(17)34080-2] [PMID: 8144628]
[22]
Kardani, K.; Bolhassani, A. CPPsite 2.0: An available database of experimentally validated cell-penetrating peptides predicting their secondary and tertiary structures. J. Mol. Biol., 2021, 433(11), 166703.
[http://dx.doi.org/10.1016/j.jmb.2020.11.002] [PMID: 33186582]
[23]
Zarei, M.; Rahbar, M.R.; Negahdaripour, M.; Morowvat, M.H.; Nezafat, N.; Ghasemi, Y. Cell penetrating peptide: Sequence-based computational prediction for intercellular delivery of arginine deiminase. Curr. Proteomics, 2020, 17(2), 117-131.
[http://dx.doi.org/10.2174/1570164616666190701120351]
[24]
Pundir, S.; Martin, M.J.; O’Donovan, C. UniProt Protein Knowledgebase. In: Protein bioinformatics. Methods in molecular biology; Wu, C.; Arighi, C.; Ross, K., Eds.; Humana Press: New York, NY, 2017; pp. 41-55.
[http://dx.doi.org/10.1007/978-1-4939-6783-4_2]
[25]
Gautam, A.; Chaudhary, K.; Kumar, R.; Raghava, G.P.S. Computer-aided virtual screening and designing of cell-penetrating peptides. Methods Mol. Biol., 2015, 1324, 59-69.
[http://dx.doi.org/10.1007/978-1-4939-2806-4_4]
[26]
Gasteiger, E.; Hoogland, C.; Gattiker, A.; Wilkins, M.R.; Appel, R.D.; Bairoch, A. Protein Identification and Analysis Tools on the ExPASy Server. In: The proteomics protocols handbook The proteomics protocols handbook; Springer Protocols Handbooks, 2005; pp. 571-607.
[http://dx.doi.org/10.1385/1-59259-890-0:571]
[27]
Doytchinova, I.A.; Flower, D.R. VaxiJen: A server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinformatics, 2007, 8(1), 4.
[http://dx.doi.org/10.1186/1471-2105-8-4] [PMID: 17207271]
[28]
Almagro Armenteros, J.J.; Sønderby, C.K.; Sønderby, S.K.; Nielsen, H.; Winther, O. DeepLoc: Prediction of protein subcellular localization using deep learning. Bioinformatics, 2017, 33(21), 3387-3395.
[http://dx.doi.org/10.1093/bioinformatics/btx431] [PMID: 29036616]
[29]
Yang, J.; Yan, R.; Roy, A.; Xu, D.; Poisson, J.; Zhang, Y. The I-TASSER Suite: Protein structure and function prediction. Nat. Methods, 2015, 12(1), 7-8.
[http://dx.doi.org/10.1038/nmeth.3213] [PMID: 25549265]
[30]
Laskowski, R.; MacArthur, M.; Thornton, J. PROCHECK: Validation of Protein-Structure Coordinates. In: Crystallography of biological macromolecules; , 2006.
[http://dx.doi.org/10.1107/97809553602060000882]
[31]
Colovos, C.; Yeates, T.O. Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Sci., 1993, 2(9), 1511-1519.
[http://dx.doi.org/10.1002/pro.5560020916] [PMID: 8401235]
[32]
Lüthy, R.; Bowie, J.U.; Eisenberg, D. Assessment of protein models with three-dimensional profiles. Nature, 1992, 356(6364), 83-85.
[http://dx.doi.org/10.1038/356083a0] [PMID: 1538787]
[33]
Wiederstein, M.; Sippl, M.J. ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res., 2007, 35(S2), W407-W410.
[http://dx.doi.org/10.1093/nar/gkm290] [PMID: 17517781]
[34]
Li, Y.; Rosal, R.V.; Brandt-Rauf, P.W.; Fine, R.L. Correlation between hydrophobic properties and efficiency of carrier-mediated membrane transduction and apoptosis of a p53 C-terminal peptide. Biochem. Biophys. Res. Commun., 2002, 298(3), 439-449.
[http://dx.doi.org/10.1016/S0006-291X(02)02470-1] [PMID: 12413961]
[35]
Nam, S.H.; Park, J.; Koo, H. Recent advances in selective and targeted drug/gene delivery systems using cell-penetrating peptides. Arch. Pharm. Res., 2023, 46(1), 18-34.
[http://dx.doi.org/10.1007/s12272-022-01425-y] [PMID: 36593377]
[36]
Yokoyama, Y.; Ramakrishnan, S. Improved biological activity of a mutant endostatin containing a single amino-acid substitution. Br. J. Cancer, 2004, 90(8), 1627-1635.
[http://dx.doi.org/10.1038/sj.bjc.6601745] [PMID: 15083196]
[37]
Xu, X.; Mao, W.; Chen, Q.; Zhuang, Q.; Wang, L.; Dai, J.; Wang, H.; Huang, Z. Endostar, a modified recombinant human endostatin, suppresses angiogenesis through inhibition of Wnt/β-catenin signaling pathway. PLoS One, 2014, 9(9), e107463.
[http://dx.doi.org/10.1371/journal.pone.0107463] [PMID: 25232946]
[38]
Hansen, M.; Kilk, K.; Langel, Ü. Predicting cell-penetrating peptides. Adv. Drug Deliv. Rev., 2008, 60(4-5), 572-579.
[http://dx.doi.org/10.1016/j.addr.2007.09.003] [PMID: 18045726]

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