Recombinant Active Peptides and their Therapeutic Functions

Ya’u   Sabo    Ajingi; Neeranuch      Rukying; Aiyada      Aroonsri; Nujarin      Jongruja
Abstract

Abstract: Recombinant active peptides are utilized as diagnostic and biotherapeutics in various maladies and as bacterial growth inhibitors in the food industry. This consequently stimulated the need for recombinant peptides' production, which resulted in about 19 approved biotech peptides of 1- 100 amino acids commercially available. While most peptides have been produced by chemical synthesis, the production of lengthy and complicated peptides comprising natural amino acids has been problematic with low quantity. Recombinant peptide production has become very vital, costeffective, simple, environmentally friendly with satisfactory yields. Several reviews have focused on discussing expression systems, advantages, disadvantages, and alternatives strategies. Additionally, the information on the antimicrobial activities and other functions of multiple recombinant peptides is challenging to access and is scattered in literature apart from the food and drug administration (FDA) approved ones. From the reports that come to our knowledge, there is no existing review that offers substantial information on recombinant active peptides developed by researchers and their functions. This review provides an overview of some successfully produced recombinant active peptides of ≤100 amino acids by focusing on their antibacterial, antifungal, antiviral, anticancer, antioxidant, antimalarial, and immune-modulatory functions. It also elucidates their modes of expression that could be adopted and applied in future investigations. We expect that the knowledge available in this review would help researchers involved in recombinant active peptide development for therapeutic uses and other applications.
Keywords: Recombinant peptides, antimicrobial, antihypertensive, immunomodulatory, antioxidant functions, expression systems, anticancer, antimalaria.
Graphical Abstract

[1] 
Otvos, L.; Wade, J.D. Current challenges in peptide-based drug discovery. Front Chem.,  2014, 2, 8-11.
[http://dx.doi.org/10.3389/fchem.2014.00062] 
[2] 
Analysis, A. Development trends for peptide therapeutics. Development,  2008, 2010, 46.
[3] 
Lax, R. The future of peptide development in the pharmaceutical industry. PharManufact; Int. Peptide Rev, 2010, pp. 10-15.
[4] 
Jaradat, D.M.M. Thirteen decades of peptide synthesis: Key developments in solid phase peptide synthesis and amide bond formation utilized in peptide ligation. Amino Acids,  2018, 50(1), 39-68.
[http://dx.doi.org/10.1007/s00726-017-2516-0] 
[5] 
Hackenberger, C.P.R.; Schwarzer, D. Chemoselective ligation and modification strategies for peptides and proteins. Angew. Chem. Int. Ed.,  2008, 47(52), 10030-10074.
[http://dx.doi.org/10.1002/anie.200801313] 
[6] 
Funfrock, P. Challenges in chemical and recombinant peptide production processes.Available from:, https://www.proteogenix.science [Accessed May 6, 2020]
[7] 
Palomares, L.A.; Estrada-Mondaca, S.; Ramírez, O. T. Production
	of recombinant proteins: Challenges and solutions. Recomb. Gene
	Expr., 2004, 267, 015-052., 
[http://dx.doi.org/10.1385/1-59259-774-2:015] 
[8] 

ClinicalTrials. drug approvals: Are more likely to be approved as pipeline recombiant.Available from:,  https://www.clinicaltrialsarena.com/comment/synthetic-peptide-drugs-less-likely-to-be-approved-than-recombinant-peptide-drugs/[Accessed Sep 9, 2020]
[9] 

 U.S. food & drug administration. Impact story: Developing the
	tools to evaluate complex drug products: peptides. FDA, Available
	from: , https://www.fda.gov/drugs/regulatory-science-action/impact-story-developing-tools-evaluate-complex-drug-products-peptides [Accessed Sep 9, 2020]
[10] 
Lau, J.L.; Dunn, M.K. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg. Med. Chem.,  2018, 26(10), 2700-2707.
[http://dx.doi.org/10.1016/j.bmc.2017.06.052] 
[11] 
Wegmuller, S.; Schmid, S. Recombinant peptide production in microbial cells. Curr. Org. Chem.,  2014, 18(8), 1005-1019.
[http://dx.doi.org/10.2174/138527281808140616160013] 
[12] 

 Lloyd, Ian Pharma r&d annual review 2019 l pharma intelligence	2019. Available from:, https://pharmaintelligence.informa.com/resources/product-content/pharma-rnd-annual-review-[Accessed	Sep 9, 2020]
[13] 

Blaskovich, Mark Explainer: Peptides vs. proteins - What’s the	difference? Available from:, https://imb.uq.edu.au/article/2017/11/explainer-peptides-vs-proteins-whats-difference [Accessed Sep 9,2020]
[14] 
Gaiser, R.A.; Rivas, L.; Lopes, P. Production of eukaryotic antimicrobial peptides by bacteria: A review.In: Science against Microbial Pathogens: Communicating Current Research and Technological Advances; Formatex, 2011, pp. 978-988.
[15] 
Li, Y. Recombinant production of antimicrobial peptides in Escherichia coli: A review. Protein Expr. Purif.,  2011, 80(2), 260-267.
[http://dx.doi.org/10.1016/j.pep.2011.08.001] 
[16] 
Ingham, A.B.; Moore, R.J. Recombinant production of antimicrobial peptides in heterologous microbial systems. Biotechnol. Appl. Biochem.,  2007, 47(1), 1-9.
[http://dx.doi.org/10.1042/BA20060207] 
[17] 
Parachin, N.S.; Mulder, K.C.; Viana, A.A.B.; Dias, S.C.; Franco, O.L. Expression systems for heterologous production of antimicrobial peptides. Peptides,  2012, 38(2), 446-456.
[http://dx.doi.org/10.1016/j.peptides.2012.09.020] 
[18] 
Huang, C-J.; Lin, H.; Yang, X. Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements. J. Ind. Microbiol. Biotechnol.,  2012, 39(3), 383-399.
[http://dx.doi.org/10.1007/s10295-011-1082-9] 
[19] 
Ahmad, M.; Hirz, M.; Pichler, H.; Schwab, H. Protein expression in Pichia pastoris: Recent achievements and perspectives for heterologous protein production. Appl. Microbiol. Biotechnol.,  2014, 98(12), 5301-5317.
[http://dx.doi.org/10.1007/s00253-014-5732-5] 
[20] 
Merlin, M.; Gecchele, E.; Capaldi, S.; Pezzotti, M.; Avesani, L. Comparative evaluation of recombinant protein production in
different biofactories: The green perspective. Biomed Res. Int.,
	2014, 2014, 
[21] 
Felberbaum, R.S. The baculovirus expression vector system: A commercial manufacturing platform for viral vaccines and gene therapy vectors. Biotechnol. J.,  2015, 10(5), 702-714.
[http://dx.doi.org/10.1002/biot.201400438] 
[22] 
Gharelo, R.S.; Oliaei, E.D.; Bandehagh, A.; Khodadadi, E.; Noparvar, P.M. Production of therapeutic proteins through plant tissue and cell culture. J. Biosci. Biotechnol.,  2016, 5(1)
[23] 
McKenzie, E.A.; Abbott, W.M. Expression of recombinant proteins in insect and mammalian cells. Methods,  2018, 147, 40-49.
[http://dx.doi.org/10.1016/j.ymeth.2018.05.013] 
[24] 
Gupta, S.K.; Dangi, A.K.; Smita, M.; Dwivedi, S.; Shukla, P. Effectual bioprocess development for protein production.In: Applied microbiology and bioengineering; Elsevier, 2019, pp. 203-227.
[http://dx.doi.org/10.1016/B978-0-12-815407-6.00011-3] 
[25] 
Khan, K. Gene expression systems and recombinant protein purification. Res. J. Pharm. Biol. Chem. Sci.,  2014, 5(6), 450-463.
[26] 
Demain, A.L.; Vaishnav, P. Production of recombinant proteins by microbes and higher organisms. Biotechnol. Adv.,  2009, 27(3), 297-306.
[http://dx.doi.org/10.1016/j.biotechadv.2009.01.008] 
[27] 
Terpe, K. Overview of bacterial expression systems for heterologous protein production: From molecular and biochemical fundamentals to commercial systems. Appl. Microbiol. Biotechnol.,  2006, 72(2), 211.
[http://dx.doi.org/10.1007/s00253-006-0465-8] 
[28] 
Freudl, R. Staphylococcus carnosus and other gram-positive bacteria.In: Production of recombinant proteins; Wiley Online Library, 2005, pp. 67-87.
[http://dx.doi.org/10.1002/3527603670.ch4] 
[29] 
Gellissen, G.; Strasser, A.W.M.; Suckow, M. Key and criteria to the selection of an expression platform.In: Prod. Recomb. proteins-Novel Microb; Eukaryot. Expr. Syst, 2005, pp. 1-5.
[30] 
Ilgen, C.; Lin-Cereghino, J.; Cregg, J.M. Pichia pastoris.In: Production of recombinant proteins-novel microbial and eukaryotic expression systems; Gellissen, G., Ed.; Wiley-VCH: Weinheim, 2005. 
[http://dx.doi.org/10.1002/3527603670.ch7] 
[31] 
Altenbuchner, J.; Mattes, R. Escherichia coli. Production of Recombinant Proteins.Prod. Recomb. proteins; Wiley-VCH: Washington, DC, 2004. 
[32] 
Porro, D.; Gasser, B.; Fossati, T.; Maurer, M.; Branduardi, P.; Sauer, M.; Mattanovich, D. Production of recombinant proteins and metabolites in yeasts. Appl. Microbiol. Biotechnol.,  2011, 89(4), 939-948.
[http://dx.doi.org/10.1007/s00253-010-3019-z] 
[33] 
Baeshen, M.N.; Al-Hejin, A.M.; Bora, R.S.; Ahmed, M.M.; Ramadan, H.A.; Saini, K.S.; Baeshen, N.A.; Redwan, E.M. Production of biopharmaceuticals in E. coli: Current scenario and future perspectives. J. Microbiol. Biotechnol.,  2015, 25(7), 953-962.
[http://dx.doi.org/10.4014/jmb.1412.12079] 
[34] 
Gupta, S.K.; Shukla, P. Advanced technologies for improved expression of recombinant proteins in bacteria: Perspectives and applications. Crit. Rev. Biotechnol.,  2016, 36(6), 1089-1098.
[http://dx.doi.org/10.3109/07388551.2015.1084264] 
[35] 
Tripathi, N.K.; Shrivastava, A. Recent developments in bioprocessing of recombinant proteins: Expression hosts and process development. Front. Bioeng. Biotechnol.,  2019, 7.
[http://dx.doi.org/10.3389/fbioe.2019.00420] 
[36] 
Liu, M.; Wang, B.; Wang, F.; Yang, Z.; Gao, D.; Zhang, C.; Ma, L.; Yu, X. Soluble expression of single-chain variable fragment (scfv) in Escherichia coli using superfolder green fluorescent protein as fusion partner. Appl. Microbiol. Biotechnol.,  2019, 103(15), 6071-6079.
[http://dx.doi.org/10.1007/s00253-019-09925-6] 
[37] 
Malekian, R.; Sima, S.; Jahanian-Najafabadi, A.; Moazen, F.; Akbari, V. Improvement of soluble expression of gm-csf in the cytoplasm of Escherichia coli using chemical and molecular chaperones. Protein Expr. Purif.,  2019, 160, 66-72.
[http://dx.doi.org/10.1016/j.pep.2019.04.002] 
[38] 
Mamat, U.; Wilke, K.; Bramhill, D.; Schromm, A.B.; Lindner, B.; Kohl, T.A.; Corchero, J.L.; Villaverde, A.; Schaffer, L.; Head, S.R.; Souvignier, C.; Meredith, T.C.; Woodard, R.W. Detoxifying Escherichia coli for endotoxin-free production of recombinant proteins. Microb. Cell Fact.,  2015, 14(1), 1-15.
[39] 
Ferrer-Miralles, N.; Domingo-Espin, J.; Corchero, J.L.; Vázquez, E.; Villaverde, A. Microbial factories for recombinant pharmaceuticals. Microb. Cell Fact.,  2009, 8(1), 17.
[http://dx.doi.org/10.1186/1475-2859-8-17] 
[40] 
Wacker, M.; Linton, D.; Hitchen, P. G.; Nita-Lazar, M.; Haslam, S. M.; North, S. J.; Panico, M.; Morris, H. R.; Dell, A.; Wren, B. W.; Aebi, M. .N-linked glycosylation in Campylobacter jejuni and its
	functional transfer into E. coli. Science (80-), 2002, 298(5599),
	1790-1793., 
[41] 
Valderrama-Rincon, J.D.; Fisher, A.C.; Merritt, J.H.; Fan, Y-Y.; Reading, C.A.; Chhiba, K.; Heiss, C.; Azadi, P.; Aebi, M.; DeLisa, M.P. An engineered eukaryotic protein glycosylation pathway in Escherichia coli. Nat. Chem. Biol.,  2012, 8(5), 434.
[http://dx.doi.org/10.1038/nchembio.921] 
[42] 
Rosano, G.L.; Ceccarelli, E.A. Recombinant protein expression in Escherichia coli: Advances and challenges. Front. Microbiol.,  2014, 5, 172.
[http://dx.doi.org/10.3389/fmicb.2014.00172] 
[43] 
Rosano, G.L.; Morales, E.S.; Ceccarelli, E.A. New tools for recombinant protein production in Escherichia coli: A 5-year update. Protein Sci.,  2019, 28(8), 1412-1422.
[http://dx.doi.org/10.1002/pro.3668] 
[44] 
Chen, R. Bacterial expression systems for recombinant protein production: E. coli and beyond. Biotechnol. Adv.,  2012, 30(5), 1102-1107.
[http://dx.doi.org/10.1016/j.biotechadv.2011.09.013] 
[45] 
Hayat Khan, K. Gene expression in mammalian cells and its applications. Adv. Pharm. Bull.,  2013, 3(2), 257-263.
[http://dx.doi.org/10.5681/apb] 
[46] 
Nielsen, J. Production of biopharmaceutical proteins by yeast: Advances through metabolic engineering. Bioengineered,  2013, 4(4), 207-211.
[http://dx.doi.org/10.4161/bioe.22856] 
[47] 
Fletcher, E.; Krivoruchko, A.; Nielsen, J. Industrial systems biology and its impact on synthetic biology of yeast cell factories. Biotechnol. Bioeng.,  2016, 113(6), 1164-1170.
[http://dx.doi.org/10.1002/bit.25870] 
[48] 
Vieira Gomes, A.M.; Souza Carmo, T.; Silva Carvalho, L.; Mendonça Bahia, F.; Parachin, N.S. Comparison of yeasts as hosts for recombinant protein production. Microorganisms,  2018, 6(2), 38.
[http://dx.doi.org/10.3390/microorganisms6020038] 
[49] 
Baghban, R.; Farajnia, S.; Rajabibazl, M.; Ghasemi, Y.; Mafi, A.; Hoseinpoor, R.; Rahbarnia, L.; Aria, M. Yeast expression systems: Overview and recent advances. Mol. Biotechnol.,  2019, 61(5), 365-384.
[http://dx.doi.org/10.1007/s12033-019-00164-8] 
[50] 
Huertas, M.J.; Michán, C. Paving the way for the production of secretory proteins by yeast cell factories. Microb. Biotechnol.,  2019, 12(6), 1095.
[http://dx.doi.org/10.1111/1751-7915.13342] 
[51] 
Huang, M.; Wang, G.; Qin, J.; Petranovic, D.; Nielsen, J. Engineering the protein secretory pathway of Saccharomyces cerevisiae enables improved protein production. Proc. Natl. Acad. Sci. USA,  2018, 115(47), E11025-E11032.
[http://dx.doi.org/10.1073/pnas.1809921115] 
[52] 
Gupta, S.K.; Shukla, P. Sophisticated cloning, fermentation, and purification technologies for an enhanced therapeutic protein production: A review. Front. Pharmacol.,  2017, 8, 419.
[http://dx.doi.org/10.3389/fphar.2017.00419] 
[53] 
Looser, V.; Bruhlmann, B.; Bumbak, F.; Stenger, C.; Costa, M.; Camattari, A.; Fotiadis, D.; Kovar, K. Cultivation strategies to enhance productivity of Pichia pastoris: A review. Biotechnol. Adv.,  2015, 33(6), 1177-1193.
[http://dx.doi.org/10.1016/j.biotechadv.2015.05.008] 
[54] 
Juturu, V.; Wu, J.C. Heterologous protein expression in Pichia pastoris: Latest research progress and applications. ChemBioChem,  2018, 19(1), 7-21.
[http://dx.doi.org/10.1002/cbic.201700460] 
[55] 
Yang, Z.; Zhang, Z. Engineering strategies for enhanced production of protein and bio-products in Pichia pastoris: A review. Biotechnol. Adv.,  2018, 36(1), 182-195.
[http://dx.doi.org/10.1016/j.biotechadv.2017.11.002] 
[56] 
Werten, M.W.T.; Eggink, G.; Stuart, M.A.C.; de Wolf, F.A. Production of protein-based polymers in Pichia pastoris. Biotechnol. Adv.,  2019, 37(5), 642-666.
[http://dx.doi.org/10.1016/j.biotechadv.2019.03.012] 
[57] 
Sinha, J.; Plantz, B.A.; Inan, M.; Meagher, M.M. Causes of proteolytic degradation of secreted recombinant proteins produced in methylotrophic yeast Pichia pastoris: Case study with recombinant ovine interferon-τ. Biotechnol. Bioeng.,  2005, 89(1), 102-112.
[http://dx.doi.org/10.1002/bit.20318] 
[58] 
Zhang, Y.; Liu, R.; Wu, X. The proteolytic systems and heterologous proteins degradation in the methylotrophic yeast Pichia pastoris. Ann. Microbiol.,  2007, 57(4), 553.
[http://dx.doi.org/10.1007/BF03175354] 
[59] 
Dyo, Y.M.; Purton, S. The algal chloroplast as a synthetic biology platform for production of therapeutic proteins. Microbiology,  2018, 164, 113-121.
[http://dx.doi.org/10.1099/mic.0.000599] 
[60] 
Havlik, D.; Brandt, U.; Bohle, K.; Fleißner, A. Establishment of Neurospora crassa as a host for heterologous protein production using a human antibody fragment as a model product. Microb. Cell Fact.,  2017, 16(1), 128.
[http://dx.doi.org/10.1186/s12934-017-0734-5] 
[61] 
Magaña-Ortiz, D.; Fernández, F.; Loske, A.M.; Gómez-Lim, M.A. Extracellular expression in Aspergillus niger of an antibody fused to leishmania sp. antigens. Curr. Microbiol.,  2018, 75(1), 40-48.
[http://dx.doi.org/10.1007/s00284-017-1348-1] 
[62] 
Contreras-Gómez, A.; Sánchez-Mirón, A.; Garcia-Camacho, F.; Molina-Grima, E.; Chisti, Y. Protein production using the baculovirus-insect cell expression system. Biotechnol. Prog.,  2014, 30(1), 1-18.
[http://dx.doi.org/10.1002/btpr.1842] 
[63] 
Kost, T.A.; Kemp, C.W. Fundamentals of baculovirus expression and applications.In: Advanced Technologies for Protein Complex Production and Characterization; Springer, 2016, pp. 187-197.
[http://dx.doi.org/10.1007/978-3-319-27216-0_12] 
[64] 
Gecchele, E.; Merlin, M.; Brozzetti, A.; Falorni, A.; Pezzotti, M.; Avesani, L. A comparative analysis of recombinant protein expression in different biofactories: Bacteria, insect cells and plant systems. J. Vis. Exp., 2015, (97)e52459
[http://dx.doi.org/10.3791/52459] 
[65] 
Van Oers, M.M.; Pijlman, G.P.; Vlak, J.M. Thirty years of baculovirus-insect cell protein expression: From dark horse to mainstream technology. J. Gen. Virol.,  2015, 96(1), 6-23.
[http://dx.doi.org/10.1099/vir.0.067108-0] 
[66] 
Yee, C.M.; Zak, A.J.; Hill, B.D.; Wen, F. The coming age of insect cells for manufacturing and development of protein therapeutics. Ind. Eng. Chem. Res.,  2018, 57(31), 10061-10070.
[http://dx.doi.org/10.1021/acs.iecr.8b00985] 
[67] 
Ghasemi, A.; Bozorg, A.; Rahmati, F.; Mirhassani, R.; Hosseininasab, S. Comprehensive study on wave bioreactor system to scale up the cultivation of and recombinant protein expression in baculovirus-infected insect cells. Biochem. Eng. J.,  2019, 143, 121-130.
[http://dx.doi.org/10.1016/j.bej.2018.12.011] 
[68] 
Le, L.T.M.; Nyengaard, J.R.; Golas, M.M.; Sander, B. Vectors for expression of signal peptide-dependent proteins in baculovirus/insect cell systems and their application to expression and purification of the high-affinity immunoglobulin gamma fc receptor i in complex with its gamma chain. Mol. Biotechnol.,  2018, 60(1), 31-40.
[http://dx.doi.org/10.1007/s12033-017-0041-8] 
[69] 
Dumont, J.; Euwart, D.; Mei, B.; Estes, S.; Kshirsagar, R. Human cell lines for biopharmaceutical manufacturing: History, status, and future perspectives. Crit. Rev. Biotechnol.,  2016, 36(6), 1110-1122.
[http://dx.doi.org/10.3109/07388551.2015.1084266] 
[70] 
Bandaranayake, A.D.; Almo, S.C. Recent advances in mammalian protein production. FEBS Lett.,  2014, 588(2), 253-260.
[http://dx.doi.org/10.1016/j.febslet.2013.11.035] 
[71] 
Hunter, M.; Yuan, P.; Vavilala, D.; Fox, M. Optimization of protein expression in mammalian cells. Curr. Protoc. Protein Sci.,  2019, 95(1)e77
[http://dx.doi.org/10.1002/cpps.77] 
[72] 
Nishida, T.; Kubota, S.; Takigawa, M. Production of recombinant CCN2 protein by mammalian cells.In: CCN proteins; Springer, 2017, pp. 95-105.
[http://dx.doi.org/10.1007/978-1-4939-6430-7_10] 
[73] 
Lalonde, M-E.; Durocher, Y. Therapeutic glycoprotein production in mammalian cells. J. Biotechnol.,  2017, 251, 128-140.
[http://dx.doi.org/10.1016/j.jbiotec.2017.04.028] 
[74] 
Wang, X.; Yu, H.; Xing, R.; Li, P. Characterization, preparation, and purification of marine bioactive peptides. BioMed Res. Int.,  2017, 2017(1)
[http://dx.doi.org/10.1155/2017/9746720] 
[75] 
Heffner, K.M.; Wang, Q.; Hizal, D.B.; Can, Ö.; Betenbaugh, M.J. Glycoengineering of mammalian expression systems on a cellular level. Adv. Biochem. Eng. Biotechnol.,  2021, 175, 37-69.
[http://dx.doi.org/10.1007/10_2017_57]] 
[76] 
Maksimenko, O.G.; Deykin, A.V.; Georgiev, P.G. Use of transgenic animals in biotechnology: Prospects and problems. Acta Naturae,  2013, 5(1), 33-46.
[77] 
Houdebine, L-M. Production of pharmaceutical proteins by transgenic animals. Comp. Immunol. Microbiol. Infect. Dis.,  2009, 32(2), 107-121.
[http://dx.doi.org/10.1016/j.cimid.2007.11.005] 
[78] 
Moura, R.R.; Melo, L.M.; Freitas, V.J. de F. Production of recombinant proteins in milk of transgenic and non-transgenic goats. Braz. Arch. Biol. Technol.,  2011, 54(5), 927-938.
[http://dx.doi.org/10.1590/S1516-89132011000500010] 
[79] 
Owczarek, B.; Gerszberg, A.; Hnatuszko-Konka, K. A brief reminder of systems of production and chromatography-based recovery of recombinant protein biopharmaceuticals. BioMed Res. Int.,  2019, 2019Article ID 4216060
[http://dx.doi.org/10.1155/2019/4216060] 
[80] 
Wang, G. Database-guided discovery of potent peptides to combat HIV-1 or superbugs. Pharmaceuticals,  2013, 6(6), 728-758.
[http://dx.doi.org/10.3390/ph6060728] 
[81] 
Bertolini, L.R.; Meade, H.; Lazzarotto, C.R.; Martins, L.T.; Tavares, K.C.; Bertolini, M.; Murray, J.D. The transgenic animal platform for biopharmaceutical production. Transgenic Res.,  2016, 25(3), 329-343.
[http://dx.doi.org/10.1007/s11248-016-9933-9] 
[82] 
Monzani, P.S.; Adona, P.R.; Ohashi, O.M.; Meirelles, F.V.; Wheeler, M.B. Transgenic bovine as bioreactors: Challenges and perspectives. Bioengineered,  2016, 7(3), 123-131.
[http://dx.doi.org/10.1080/21655979.2016.1171429] 
[83] 
Barta, A.; Sommergruber, K.; Thompson, D.; Hartmuth, K.; Matzke, M.A.; Matzke, A.J.M. The expression of a nopaline synthase-human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Mol. Biol.,  1986, 6(5), 347-357.
[http://dx.doi.org/10.1007/BF00034942] 
[84] 
Fahad, S.; Khan, F.A.; Pandupuspitasari, N.S.; Ahmed, M.M.; Liao, Y.C.; Waheed, M.T.; Sameeullah, M.; Hussain, S.; Saud, S.; Hassan, S.; Jan, A.; Jan, M.T.; Wu, C.; Chun, M.X.; Huang, J. Recent developments in therapeutic protein expression technologies in plants. Biotechnol. Lett.,  2015, 37(2), 265-279.
[http://dx.doi.org/10.1007/s10529-014-1699-7] 
[85] 
Yao, J.; Weng, Y.; Dickey, A.; Wang, K.Y. Plants as factories for human pharmaceuticals: Applications and challenges. Int. J. Mol. Sci.,  2015, 16(12), 28549-28565.
[http://dx.doi.org/10.3390/ijms161226122] 
[86] 
Łojewska, E.; Kowalczyk, T.; Olejniczak, S.; Sakowicz, T. Extraction and purification methods in downstream processing of plant-based recombinant proteins. Protein Expr. Purif.,  2016, 120, 110-117.
[http://dx.doi.org/10.1016/j.pep.2015.12.018] 
[87] 
Lomonossoff, G. P.; D'Aoust, M.-A. Plant-produced biopharmaceuticals: A case of technical developments driving clinical deployment.Science (80-.), 2016, 353(6305), 1237-1240., 
[88] 
Park, K.Y.; Wi, S.J. Potential of plants to produce recombinant protein products. J. Plant Biol.,  2016, 59(6), 559-568.
[http://dx.doi.org/10.1007/s12374-016-0482-9] 
[89] 
Buyel, J.F.; Twyman, R.M.; Fischer, R. Very-large-scale production of antibodies in plants: The biologization of manufacturing. Biotechnol. Adv.,  2017, 35(4), 458-465.
[http://dx.doi.org/10.1016/j.biotechadv.2017.03.011] 
[90] 
Dirisala, V.R.; Nair, R.R.; Srirama, K.; Reddy, P.N.; Rao, K.R.S.S.; Kumar, N.S.S.; Parvatam, G. Recombinant pharmaceutical protein production in plants: Unraveling the therapeutic potential of molecular pharming. Acta Physiol. Plant.,  2017, 39(1), 18.
[http://dx.doi.org/10.1007/s11738-016-2315-3] 
[91] 
Xu, J.; Towler, M.; Weathers, P.J. Platforms for plant-based protein production. Bioprocess. Plant Vitr; Syst, 2018, p. 509.
[92] 
Rech Filho, E.L.; Vianna, G.R.; Murad, A.M.; Cunha, N.; Lacorte, C.C.; De Araujo, A.C.G.; Brigido, M.; Michael, W.; Fontes, A.; Barry, O.; Andrew, S.; Otavia, C. Recombinant proteins in plants.BMC Proc., 2014, vol. 8, suppl., P.01., 
[93] 
Fischer, R.; Holland, T.; Sack, M.; Schillberg, S.; Stoger, E.; Twyman, R.M.; Buyel, J.F. Glyco-engineering of plant-based expression systems.Advances in Glycobiotechnology; Springer Nature Switzerland AG, 2018, Vol. 175, pp. 137-166.
[http://dx.doi.org/10.1007/10_2018_76] 
[94] 
Loh, H-S.; Green, B.J.; Yusibov, V. Using transgenic plants and modified plant viruses for the development of treatments for human diseases. Curr. Opin. Virol.,  2017, 26, 81-89.
[http://dx.doi.org/10.1016/j.coviro.2017.07.019] 
[95] 
Mookherjee, N.; Hancock, R.E.W. Cationic host defence peptides: Innate immune regulatory peptides as a novel approach for treating infections. Cell. Mol. Life Sci.,  2007, 64(7–8), 922.
[http://dx.doi.org/10.1007/s00018-007-6475-6] 
[96] 
Reddy, K.V.R.; Yedery, R.D.; Aranha, C. Antimicrobial peptides: Premises and promises. Int. J. Antimicrob. Agents,  2004, 24(6), 536-547.
[http://dx.doi.org/10.1016/j.ijantimicag.2004.09.005] 
[97] 
Hancock, R.E.W.; Sahl, H-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol.,  2006, 24(12), 1551.
[http://dx.doi.org/10.1038/nbt1267] 
[98] 
Li, C.; Blencke, H.M.; Smith, L.C.; Karp, M.T.; Stensvåg, K. Two recombinant peptides, spstrongylocins 1 and 2, from Strongylocentrotus purpuratus, show antimicrobial activity against gram-positive and gram-negative bacteria. Dev. Comp. Immunol.,  2010, 34(3), 286-292.
[http://dx.doi.org/10.1016/j.dci.2009.10.006] 
[99] 
Guillén-Chable, F.; Arenas-Sosa, I.; Islas-Flores, I.; Corzo, G.; Martinez-Liu, C.; Estrada, G. Antibacterial activity and phospholipid recognition of the recombinant defensin j1-1 from capsicum genus. Protein Expr. Purif.,  2017, 136, 45-51.
[http://dx.doi.org/10.1016/j.pep.2017.06.007] 
[100] 
Zhang, L.; Yang, D.; Wang, Q.; Yuan, Z.; Wu, H.; Pei, D.; Cong, M.; Li, F.; Ji, C.; Zhao, J. A defensin from clam Venerupis philippinarum: Molecular characterization, localization, antibacterial activity, and mechanism of action. Dev. Comp. Immunol.,  2015, 51(1), 29-38.
[http://dx.doi.org/10.1016/j.dci.2015.02.009] 
[101] 
Meng, D.M.; Lv, Y.J.; Zhao, J.F.; Liu, Q.Y.; Shi, L.Y.; Wang, J.P.; Yang, Y.H.; Fan, Z.C. Efficient production of a recombinant Venerupis philippinarum defensin (vpdef) in Pichia pastoris and characterization of its antibacterial activity and stability. Protein Expr. Purif.,  2017, 2018(147), 78-84.
[http://dx.doi.org/10.1016/j.pep.2018.03.001] 
[102] 
Tseng, J-M.; Huang, J-R.; Huang, H-C.; Tzen, J.T.C.; Chou, W-M.; Peng, C-C. Facilitative production of an antimicrobial peptide royalisin and its antibody via an artificial oil-body system. Biotechnol. Prog.,  2011, 27(1), 153-161.
[http://dx.doi.org/10.1002/btpr.528] 
[103] 
Bílikova, K.; Huang, S.C.; Lin, I.P.; Šimuth, J.; Peng, C.C. Structure and antimicrobial activity relationship of royalisin, an antimicrobial peptide from royal jelly of apis mellifera. Peptides,  2015, 68, 190-196.
[http://dx.doi.org/10.1016/j.peptides.2015.03.001] 
[104] 
Kuddus, M.R.; Rumi, F.; Tsutsumi, M.; Takahashi, R.; Yamano, M.; Kamiya, M.; Kikukawa, T.; Demura, M.; Aizawa, T. Expression, purification and characterization of the recombinant cysteine-rich antimicrobial peptide snakin-1 in Pichia pastoris. Protein Expr. Purif.,  2016, 122, 15-22.
[http://dx.doi.org/10.1016/j.pep.2016.02.002] 
[105] 
Scocchi, M.; Zelezetsky, I.; Benincasa, M.; Gennaro, R.; Mazzoli, A.; Tossi, A. Structural aspects and biological properties of the cathelicidin pmap-36. FEBS J.,  2005, 272(17), 4398-4406.
[http://dx.doi.org/10.1111/j.1742-4658.2005.04852.x] 
[106] 
Storici, P.; Scocchi, M.; Tossi, A.; Gennaro, R.; Zanetti, M. Chemical synthesis and biological activity of a novel antibacterial peptide deduced from a pig myeloid CDNA. FEBS Lett.,  1994, 337(3), 303-307.
[http://dx.doi.org/10.1016/0014-5793(94)80214-9] 
[107] 
Lv, Y.; Wang, J.; Gao, H.; Wang, Z.; Dong, N.; Ma, Q.; Shan, A. Antimicrobial properties and membrane-active mechanism of a potential $α$-helical antimicrobial derived from cathelicidin pmap-36. PLoS One,  2014, 9(1)
[http://dx.doi.org/10.1371/journal.pone.0086364] 
[108] 
Lyu, Y.; Yang, Y.; Lyu, X.; Dong, N.; Shan, A. Antimicrobial activity, improved cell selectivity and mode of action of short pmap-36-derived peptides against bacteria and candida. Sci. Rep.,  2016, 6, 27258.
[http://dx.doi.org/10.1038/srep27258] 
[109] 
Rao, Z.; Kim, S.Y.; Akanda, M.R.; Lee, S.J.; Jung, I.D.; Park, B.Y.; Kamala-Kannan, S.; Hur, J.; Park, J.H. Enhanced expression and functional characterization of the recombinant putative lysozyme-pmap36 fusion protein. Mol. Cells,  2019, 42(3), 262-269.
[http://dx.doi.org/10.14348/molcells.2019.2365] 
[110] 
Saugar, J.M.; Rodriguez-Hernández, M.J.; Beatriz, G.; Pachón-Ibañez, M.E.; Fernández-Reyes, M.; Andreu, D.; Pachón, J.; Rivas, L. Activity of cecropin a-melittin hybrid peptides against colistin-resistant clinical strains of Acinetobacter baumannii: Molecular basis for the differential mechanisms of action. Antimicrob. Agents Chemother.,  2006, 50(4), 1251-1256.
[http://dx.doi.org/10.1128/AAC.50.4.1251-1256.2006] 
[111] 
Tan, T.; Wu, D.; Li, W.; Zheng, X.; Li, W.; Shan, A. High specific selectivity and membrane-active mechanism of synthetic cationic hybrid antimicrobial peptides based on the peptide fv7. Int. J. Mol. Sci.,  2017, 18(2), 339.
[http://dx.doi.org/10.3390/ijms18020339] 
[112] 
Thennarasu, S.; Tan, A.; Penumatchu, R.; Shelburne, C.E.; Heyl, D.L.; Ramamoorthy, A. Antimicrobial and membrane disrupting activities of a peptide derived from the human cathelicidin antimicrobial peptide ll37. Biophys. J.,  2010, 98(2), 248-257.
[http://dx.doi.org/10.1016/j.bpj.2009.09.060] 
[113] 
Ramos, R.; Domingues, L.; Gama, M. LL37, a human antimicrobial peptide with immunomodulatory properties. Sci. against. Microb. Pathog.,  2011, 915-925.
[114] 
Wang, G. Human antimicrobial peptides and proteins. Pharmaceuticals,  2014, 7(5), 545-594.
[http://dx.doi.org/10.3390/ph7050545] 
[115] 
Giacometti, A.; Cirioni, O.; Kamysz, W.; D’Amato, G.; Silvestri, C.; Del Prete, M.S.; Łukasiak, J.; Scalise, G. Comparative activities of cecropin a, melittin, and cecropin a- melittin peptide ca (1--7) m (2--9) nh2 against multidrug-resistant nosocomial isolates of Acinetobacter baumannii. Peptides,  2003, 24(9), 1315-1318.
[http://dx.doi.org/10.1016/j.peptides.2003.08.003] 
[116] 
Bacalum, M.; Radu, M. Cationic antimicrobial peptides cytotoxicity on mammalian cells: An analysis using therapeutic index integrative concept. Int. J. Pept. Res. Ther.,  2015, 21(1), 47-55.
[http://dx.doi.org/10.1007/s10989-014-9430-z] 
[117] 
Wei, X-B.; Wu, R-J.; Si, D-Y.; Liao, X-D.; Zhang, L-L.; Zhang, R-J. Novel hybrid peptide cecropin a (1-8)-ll37 (17-30) with potential antibacterial activity. Int. J. Mol. Sci.,  2016, 17(7), 983.
[http://dx.doi.org/10.3390/ijms17070983] 
[118] 
Wei, X.; Wu, R.; Zhang, L.; Ahmad, B.; Si, D.; Zhang, R. Expression, purification, and characterization of a novel hybrid peptide with potent antibacterial activity. Molecules,  2018, 23(6)
[http://dx.doi.org/10.3390/molecules23061491] 
[119] 
Al Souhail, Q.; Hiromasa, Y.; Rahnamaeian, M.; Giraldo, M.C.; Takahashi, D.; Valent, B.; Vilcinskas, A.; Kanost, M.R. Characterization and regulation of expression of an antifungal peptide from hemolymph of an insect, Manduca sexta. Dev. Comp. Immunol.,  2016, 61, 258-268.
[http://dx.doi.org/10.1016/j.dci.2016.03.006] 
[120] 
Yamane, E.S.; Bizerra, F.C.; Oliveira, E.B.; Moreira, J.T.; Rajabi, M.; Nunes, G.L.C.; De Souza, A.O.; Da Silva, I.D.C.G.; Yamane, T.; Karpel, R.L.; Silva, P.I., Jr; Hayashi, M.A.F. Unraveling the antifungal activity of a south american rattlesnake toxin crotamine. Biochimie,  2013, 95(2), 231-240.
[http://dx.doi.org/10.1016/j.biochi.2012.09.019] 
[121] 
Zhang, J.; Movahedi, A.; Wang, X.; Wu, X.; Yin, T.; Zhuge, Q. Molecular structure, chemical synthesis, and antibacterial activity of abp-dhc-cecropin a from drury (Hyphantria cunea). Peptides,  2015, 68, 197-204.
[http://dx.doi.org/10.1016/j.peptides.2014.09.011] 
[122] 
Zhang, J.; Movahedi, A.; Xu, J.; Wang, M.; Wu, X.; Xu, C.; Yin, T.; Zhuge, Q. In vitro production and antifungal activity of peptide abp-dhc-cecropin A. J. Biotechnol.,  2015, 199, 47-54.
[http://dx.doi.org/10.1016/j.jbiotec.2015.02.018] 
[123] 
Astafieva, A.A.; Rogozhin, E.A.; Andreev, Y.A.; Odintsova, T.I.; Kozlov, S.A.; Grishin, E.V.; Egorov, T.A. A novel cysteine-rich antifungal peptide toamp4 from Taraxacum officinale wigg. flowers. Plant Physiol. Biochem.,  2013, 70, 93-99.
[http://dx.doi.org/10.1016/j.plaphy.2013.05.022] 
[124] 
De Beer, A.; Vivier, M.A. Vv-AMP1, a ripening induced peptide from Vitis vinifera shows strong antifungal activity. BMC Plant Biol.,  2008, 8, 1-16.
[http://dx.doi.org/10.1186/1471-2229-8-75] 
[125] 
Picart, P.; Pirttilä, A.M.; Raventos, D.; Kristensen, H.H.; Sahl, H.G. Identification of defensin-encoding genes of Picea glauca: Characterization of pgd5, a conserved spruce defensin with strong antifungal activity. BMC Plant Biol.,  2012, 12.
[http://dx.doi.org/10.1186/1471-2229-12-180] 
[126] 
Yamano, Y.; Matsumoto, M.; Inoue, K.; Kawabata, T. Cloning of cdnas for cecropins A and B, and expression of the genes in the silkworm, Bombyx mori. Biosci. Biotechnol. Biochem.,  1994, 58(8), 1476-1478.
[http://dx.doi.org/10.1271/bbb.58.1476] 
[127] 
Yamano, Y.; Matsumoto, M.; Sasahara, K.; Sakamoto, E.; Morishima, I. Structure of genes for cecropin a and an inducible nuclear protein that binds to the promoter region of the genes from the silkworm, Bombyx mori. Biosci. Biotechnol. Biochem.,  1998, 62(2), 237-241.
[http://dx.doi.org/10.1271/bbb.62.237] 
[128] 
Yang, J.; Furukawa, S.; Sagisaka, A.; Ishibashi, J.; Taniai, K.; Shono, T.; Yamakawa, M. CDNA cloning and gene expression of cecropin D, an antibacterial protein in the silkworm, Bombyx mori. Comp. Biochem. Physiol. B Biochem. Mol. Biol.,  1999, 122(4), 409-414.
[http://dx.doi.org/10.1016/S0305-0491(99)00015-2] 
[129] 
Cavallarin, L.; Andreu, D.; San Segundo, B. Cecropin a derived peptides are potent inhibitors of fungal plant pathogens. Mol. Plant Microbe Interact.,  1998, 11(3), 218-227.
[http://dx.doi.org/10.1094/MPMI.1998.11.3.218] 
[130] 
Xia, L.; Liu, Z.; Ma, J.; Sun, S.; Yang, J.; Zhang, F. Expression, purification and characterization of cecropin antibacterial peptide from Bombyx mori in Saccharomyces cerevisiae. Protein Expr. Purif.,  2013, 90(1), 47-54.
[http://dx.doi.org/10.1016/j.pep.2013.02.013] 
[131] 
Lee, E.; Shin, A.; Kim, Y. Anti-inflammatory activities of cecropin A and its mechanism of action. Arch. Insect Biochem. Physiol.,  2015, 88(1), 31-44.
[http://dx.doi.org/10.1002/arch.21193] 
[132] 
Lu, D.; Geng, T.; Hou, C.; Huang, Y.; Qin, G.; Guo, X. Bombyx mori cecropin a has a high antifungal activity to entomopathogenic fungus Beauveria bassiana. Gene,  2016, 583(1), 29-35.
[http://dx.doi.org/10.1016/j.gene.2016.02.045] 
[133] 
Ryazantsev, D.Y.; Rogozhin, E.A.; Dimitrieva, T.V.; Drobyazina, P.E.; Khadeeva, N.V.; Egorov, T.A.; Grishin, E.V.; Zavriev, S.K. A novel hairpin-like antimicrobial peptide from barnyard grass (Echinochloa crusgalli l.) seeds: Structure-functional and molecular-genetics characterization. Biochimie,  2014, 99(1), 63-70.
[http://dx.doi.org/10.1016/j.biochi.2013.11.005] 
[134] 
Vijayan, S.; Guruprasad, L.; Kirti, P.B. Prokaryotic expression of a constitutively expressed Tephrosia villosa defensin and its potent antifungal activity. Appl. Microbiol. Biotechnol.,  2008, 80(6), 1023-1032.
[http://dx.doi.org/10.1007/s00253-008-1648-2] 
[135] 
Yokoyama, S.; Iida, Y.; Kawasaki, Y.; Minami, Y.; Watanabe, K.; Yagi, F. The chitin-binding capability of cy-amp1 from cycad is essential to antifungal activity. J. Pept. Sci.,  2009, 15(7), 492-497.
[http://dx.doi.org/10.1002/psc.1147] 
[136] 
Baskova, I.P.; Zavalova, L.L. Polyfunctionality of lysozyme destabilase from the medicinal leech. Russ. J. Bioorganic Chem.,  2008, 34(3), 304-309.
[http://dx.doi.org/10.1134/S1068162008030096] 
[137] 
Yudina, T.G.; Guo, D.; Piskunkova, N.F.; Pavlova, I.B.; Zavalova, L.L.; Baskova, I.P. Antifungal and antibacterial functions of medicinal leech recombinant destabilase-lysozyme and its heated-up derivative. Front. Chem. Sci. Eng.,  2012, 6(2), 203-209.
[http://dx.doi.org/10.1007/s11705-012-1277-2] 
[138] 
Endy, T.P.; Rochford, R.; Yuen, K-Y.; Lei, H-Y. Emerging infectious diseases as a global health threat. Exp. Biol. Med. (Maywood),  2011, 236(8), 897-898.
[http://dx.doi.org/10.1258/ebm.2011.011i01] 
[139] 
Örtqvist Åand Blennow, M.; Carlsson, R-M.; Hanson, L.; Åand Lindberg, A.; Lindqvist, L.; Magnusson, M.; Nilsson, L.; Norlund, A.; Nyrén, O. Vaccination of children - A systematic review. Acta Paediatr.,  2010, 99, 1-192.
[140] 
Esté, J.A.; Cihlar, T. Current status and challenges of antiretroviral research and therapy. Antiviral Res.,  2010, 85(1), 25-33.
[http://dx.doi.org/10.1016/j.antiviral.2009.10.007] 
[141] 
Thakur, N.; Qureshi, A.; Kumar, M. AVPpred: Collection and prediction of highly effective antiviral peptides. Nucleic Acids Res.,  2012, 40(W1), W199-W204.
[http://dx.doi.org/10.1093/nar/gks450] 
[142] 
Wyatt, R.; Sodroski, J. The hiv-1 envelope glycoproteins:
	Fusogens, antigens, and immunogens. Science (80)., 1998,
	280(5371), 1884-1888., 
[143] 
Clapham, P.R.; McKnight, Á. Cell surface receptors, virus entry and tropism of primate lentiviruses. J. Gen. Virol.,  2002, 83(8), 1809-1829.
[http://dx.doi.org/10.1099/0022-1317-83-8-1809] 
[144] 
Delcroix-genête, D.; Quan, P.; Roger, M.; Delcroix-genête, D.; Quan, P.; Roger, M.; Hazan, U.; Nisole, S. Proteins. 2006. To Cite	This Version : HAL Id : Inserm-00081431 Retrovirology, 
[145] 
Gueguen, Y.; Garnier, J.; Robert, L.; Lefranc, M-P.; Mougenot, I.; De Lorgeril, J.; Janech, M.; Gross, P.S.; Warr, G.W.; Cuthbertson, B. PenBase, the shrimp antimicrobial peptide penaeidin database: Sequence-based classification and recommended nomenclature. Dev. Comp. Immunol.,  2006, 30(3), 283-288.
[http://dx.doi.org/10.1016/j.dci.2005.04.003] 
[146] 
Vaseeharan, B.; Shanthi, S.; Chen, J-C.; Espineira, M. Molecular cloning, sequence analysis and expression of fein-penaeidin from the haemocytes of Indian white shrimp Fenneropenaeus indicus. Results Immunol.,  2012, 2, 35-43.
[http://dx.doi.org/10.1016/j.rinim.2012.02.001] 
[147] 
Xiao, B.; Fu, Q.; Niu, S.; Li, H.; Lu, K.; Wang, S.; Yin, B.; Weng, S.; Li, C.; He, J. Penaeidins are a novel family of antiviral effectors against wssv in shrimp. bioRxiv, 2018.467571
[148] 
Cai, L.; Cai, J.; Liu, H.; Fan, D.; Peng, H.; Wang, K. Comparative biochemistry and physiology, part b recombinant medaka (Oryzias melastigmus) pro-hepcidin: Multifunctional characterization. Comp. Biochem. Physiol. Part B,  2012, 161(2), 140-147.
[http://dx.doi.org/10.1016/j.cbpb.2011.10.006] 
[149] 
Jiang, Y.; Yang, D.; Li, W.; Wang, B.; Jiang, Z.; Li, M. Original
	article antiviral activity of recombinant mouse b -defensin 3 against
	influenza a virus in vitro and in vivo. 2012, 262, 255-262., 
[150] 
Pagès, J-M.; Dimarcq, J-L.; Quenin, S.; Hetru, C. Thanatin activity on multidrug resistant clinical isolates of Enterobacter aerogenes and Klebsiella pneumoniae. Int. J. Antimicrob. Agents,  2003, 22(3), 265-269.
[http://dx.doi.org/10.1016/S0924-8579(03)00201-2] 
[151] 
Sinha, S.; Zheng, L.; Mu, Y.; Ng, W.J.; Bhattacharjya, S. Structure and interactions of a host defense antimicrobial peptide thanatin in lipopolysaccharide micelles reveal mechanism of bacterial cell agglutination. Sci. Rep.,  2017, 7(1), 1-13.
[http://dx.doi.org/10.1038/s41598-017-18102-6] 
[152] 
Mamarabadi, M.; Tanhaeian, A.; Ramezany, Y. Antifungal activity of recombinant thanatin in comparison with two plant extracts and a chemical mixture to control fungal plant pathogens. AMB Express,  2018, 8(1), Article number 180.
[http://dx.doi.org/10.1186/s13568-018-0710-4] 
[153] 
Fehlbaum, P.; Bulet, P.; Chernysh, S.; Briand, J-P.; Roussel, J-P.; Letellier, L.; Hetru, C.; Hoffmann, J.A. Structure-activity analysis of thanatin, a 21-residue inducible insect defense peptide with sequence homology to frog skin antimicrobial peptides. Proc. Natl. Acad. Sci. USA,  1996, 93(3), 1221-1225.
[http://dx.doi.org/10.1073/pnas.93.3.1221] 
[154] 
Sabokkhiz, M.A.; Tanhaeian, A.; Mamarabadi, M. Study on antiviral activity of two recombinant antimicrobial peptides against tobacco mosaic virus. Probiotics Antimicrob. Proteins,  2019, 11, 1370-1378.
[http://dx.doi.org/10.1007/s12602-019-09539-4] 
[155] 
Papo, N.; Shai, Y. Host defense peptides as new weapons in cancer treatment. Cell. Mol. Life Sci. C.,  2005, 62(7-8), 784-790.
[http://dx.doi.org/10.1007/s00018-005-4560-2] 
[156] 
Auvynet, C.; Rosenstein, Y. Multifunctional host defense peptides: Antimicrobial peptides, the small yet big players in innate and adaptive immunity. FEBS J.,  2009, 276(22), 6497-6508.
[http://dx.doi.org/10.1111/j.1742-4658.2009.07360.x] 
[157] 
Hancock, R.E.W.; Diamond, G. The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol.,  2000, 8(9), 402-410.
[http://dx.doi.org/10.1016/S0966-842X(00)01823-0] 
[158] 
Ahmad, B.; Hanif, Q.; Xubiao, W.; Lulu, Z.; Shahid, M. Expression and purification of hybrid ll-37t α 1 peptide in Pichia pastoris and evaluation of its immunomodulatory and anti-inflammatory activities by lps neutralization., 2019.10, 1-12.. 
[159] 
Wang, G.; Elliott, M.; Cogen, A.L.; Ezell, E.L.; Gallo, R.L.; Hancock, R.E.W. Structure, dynamics, and antimicrobial and immune modulatory activities of human ll-23 and its single-residue variants mutated on the basis of homologous primate cathelicidins. Biochemistry,  2012, 51(2), 653-664.
[160] 
Baitsch, D.; Bock, H.H.; Engel, T.; Telgmann, R.; Müller-Tidow, C.; Varga, G.; Bot, M.; Herz, J.; Robenek, H.; Von Eckardstein, A.; Nofer, J.R.; Apolipoprotein, E. Induces antiinflammatory phenotype in macrophages. Arterioscler. Thromb. Vasc. Biol.,  2011, 31(5), 1160-1168.
[http://dx.doi.org/10.1161/ATVBAHA.111.222745] 
[161] 
Tenger, C.; Zhou, X.; Apolipoprotein, E. Modulates immune activation by acting on the antigen-presenting cell. Immunology,  2003, 109(3), 392-397.
[http://dx.doi.org/10.1046/j.1365-2567.2003.01665.x] 
[162] 
Curtiss, L.K.; Forte, T.M.; Davis, P.A. Cord blood plasma lipoproteins inhibit mitogen-stimulated lymphocyte proliferation. J. Immunol.,  1984, 133(3), 1379-1384.
[163] 
Riddell, D.R.; Graham, A.; Owen, J.S.; Apolipoprotein, E. Inhibits platelet aggregation through the l-arginine: Nitric oxide pathway implications for vascular disease. J. Biol. Chem.,  1997, 272(1), 89-95.
[http://dx.doi.org/10.1074/jbc.272.1.89] 
[164] 
Van Den Elzen, P.; Garg, S.; León, L.; Brigl, M.; Leadbetter, E.A.; Gumperz, J.E.; Dascher, C.C.; Cheng, T-Y.; Sacks, F.M.; Illarionov, P.A. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature,  2005, 437(7060), 906-910.
[http://dx.doi.org/10.1038/nature04001] 
[165] 
Roselaar, S.E.; Daugherty, A. Apolipoprotein e-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo. J. Lipid Res.,  1998, 39(9), 1740-1743.
[http://dx.doi.org/10.1016/S0022-2275(20)32160-X] 
[166] 
de Bont, N.; Netea, M.G.; Demacker, P.N.M.; Verschueren, I.; Kullberg, B.J.; van Dijk, K.W.; van der Meer, J.W.M.; Stalenhoef, A.F.H.; Apolipoprotein, E. Knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection. J. Lipid Res.,  1999, 40(4), 680-685.
[http://dx.doi.org/10.1016/S0022-2275(20)32147-7] 
[167] 
Pane, K.; Sgambati, V.; Zanfardino, A.; Smaldone, G.; Cafaro, V.; Angrisano, T.; Pedone, E.; Gaetano, S. Di; Capasso, D.; Haney, E. F.; Izzo, V.; Varcamonti, M.; Notomista, E.; Hancock, R. E. W.; Donato, A. D.; Pizzo, E. A new cryptic cationic antimicrobial peptide from human apolipoprotein E with antibacterial activity and immunomodulatory effects on human cells. FEBS J.,  2016, 283, 2115-2131.
[http://dx.doi.org/10.1111/febs.13725]] 
[168] 
Xu, C.; Guo, Y.; Qiao, L.; Ma, L.; Cheng, Y. Recombinant expressed vasoactive intestinal peptide analogue ameliorates tnbs-induced colitis in rats. World J. Gastroenterol.,  2018, 24(6), 706-715.
[http://dx.doi.org/10.3748/wjg.v24.i6.706] 
[169] 
Snow, R.W.; Marsh, K. Malaria in africa: Progress and prospects in the decade since the Abuja declaration. Lancet,  2010, 376(9735), 137-139.
[http://dx.doi.org/10.1016/s0140-6736(10)60577-6] 
[170] 

 World malaria report 2019, 2019. Available from:, https://www.who.int/publications/i/item/9789241565721
[171] 
Dondorp, A.M.; Yeung, S.; White, L.; Nguon, C.; Day, N.P.J.; Socheat, D.; Von Seidlein, L. Artemisinin resistance: Current status and scenarios for containment. Nat. Rev. Microbiol.,  2010, 8(4), 272-280.
[http://dx.doi.org/10.1038/nrmicro2331] 
[172] 
Bell, A. Antimalarial peptides: The long and the short of it. Curr. Pharm. Des.,  2011, 17(25), 2719-2731.
[http://dx.doi.org/10.2174/138161211797416057] 
[173] 
Choi, S.J.; Parent, R.; Guillaume, C.; Deregnaucourt, C.; Delarbre, C.; Ojcius, D.M.; Montagne, J.J.; Célérier, M.L.; Phelipot, A.; Amiche, M. Isolation and characterization of psalmopeotoxin I and II: Two novel antimalarial peptides from the venom of the tarantula Psalmopoeus cambridgei. FEBS Lett.,  2004, 572(1–3), 109-117.
[http://dx.doi.org/10.1016/j.febslet.2004.07.019] 
[174] 
Carballar-Lejarazú, R.; Rodríguez, M.H.; De La Cruz Hernández-Hernández, F.; Ramos-Castañeda, J.; Possani, L.D.; Zurita-Ortega, M.; Reynaud-Garza, E.; Hernández-Rivas, R.; Loukeris, T.; Lycett, G. Recombinant scorpine: A multifunctional antimicrobial peptide with activity against different pathogens. Cell. Mol. Life Sci.,  2008, 65(19), 3081-3092.
[http://dx.doi.org/10.1007/s00018-008-8250-8] 
[175] 
Hoskin, D.W.; Ramamoorthy, A. Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta (BBA)-. Biomembranes,  2008, 1778(2), 357-375.
[http://dx.doi.org/10.1016/j.bbamem.2007.11.008] 
[176] 
Riedl, S.; Zweytick, D.; Lohner, K. Membrane-active host defense peptides-challenges and perspectives for the development of novel anticancer drugs. Chem. Phys. Lipids,  2011, 164(8), 766-781.
[http://dx.doi.org/10.1016/j.chemphyslip.2011.09.004] 
[177] 
Dathe, M.; Wieprecht, T. Structural features of helical antimicrobial peptides: Their potential to modulate activity on model membranes and biological cells. Biochim. Biophys. Acta (BBA)-. Biomembranes,  1999, 1462(1–2), 71-87.
[http://dx.doi.org/10.1016/S0005-2736(99)00201-1] 
[178] 
Lohner, K.; Blondelle, S.E. Molecular mechanisms of membrane perturbation by antimicrobial peptides and the use of biophysical studies in the design of novel peptide antibiotics. Comb. Chem. High Throughput Screen.,  2005, 8(3), 241-256.
[http://dx.doi.org/10.2174/1386207053764576] 
[179] 
Bhutia, S.K.; Maiti, T.K. Targeting tumors with peptides from natural sources. Trends Biotechnol.,  2008, 26(4), 210-217.
[http://dx.doi.org/10.1016/j.tibtech.2008.01.002] 
[180] 
Schwartz, E.F.; Diego-Garcia, E.; de la Vega, R.C.R.; Possani, L.D. Transcriptome analysis of the venom gland of the mexican scorpion Hadrurus gertschi (arachnida: Scorpiones). BMC Genomics,  2007, 8(1), 119.
[http://dx.doi.org/10.1186/1471-2164-8-119] 
[181] 
Xing, L.W.; Tian, S.X.; Gao, W.; Yang, N.; Qu, P.; Liu, D.; Jiao, J.; Wang, J.; Feng, X.J. Recombinant expression and biological characterization of the antimicrobial peptide fowlicidin-2 in Pichia pastoris. Exp. Ther. Med.,  2016, 12(4), 2324-2330.
[http://dx.doi.org/10.3892/etm.2016.3578] 
[182] 
Fan, K.; Li, H.; Wang, Z.; Du, W.; Yin, W.; Sun, Y.; Jiang, J. Expression and purification of the recombinant porcine nk-lysin in Pichia pastoris and observation of anticancer activity in vitro. Prep. Biochem. Biotechnol.,  2016, 46(1), 65-70.
[http://dx.doi.org/10.1080/10826068.2014.979206] 
[183] 
Sarangthem, V.; Kim, Y.; Singh, T.D.; Seo, B.Y.; Cheon, S.H.; Lee, Y.J.; Lee, B.H.; Park, R.W. Multivalent targeting based delivery of therapeutic peptide using ap1-elp carrier for effective cancer therapy. Theranostics,  2016, 6(12), 2235-2249.
[http://dx.doi.org/10.7150/thno.16425] 
[184] 
Sun, M.; Tang, H.; Gao, Y.; Dai, X.; Yuan, Y.; Zhang, C.; Sun, D. Constitutive expression and anticancer potency of a novel immunotoxin onconase-DV3. Oncol. Rep.,  2016, 35(4), 1987-1994.
[http://dx.doi.org/10.3892/or.2016.4570]] 
[185] 
Golias, C.; Charalabopoulos, A.; Stagikas, D.; Charalabopoulos, K.; Batistatou, A. The kinin system-bradykinin: Biological effects and clinical implications. Multiple role of the kinin system-bradykinin. Hippokratia,  2007, 11(3), 124.
[186] 
Camargo, A.C.M.; Ianzer, D.; Guerreiro, J.R.; Serrano, S.M.T. Bradykinin-potentiating peptides: Beyond captopril. Toxicon,  2012, 59(4), 516-523.
[http://dx.doi.org/10.1016/j.toxicon.2011.07.013] 
[187] 
Yang, G.; Jiang, Y.; Yang, W.; Du, F.; Yao, Y.; Shi, C.; Wang, C. Effective treatment of hypertension by recombinant Lactobacillus plantarum expressing angiotensin converting enzyme inhibitory peptide. Microb. Cell Fact., 2015, Article number: 202, 1-9., 
[http://dx.doi.org/10.1186/s12934-015-0394-2] 
[188] 
Losacco, M.; Gallerani, R.; Gobbetti, M.; Minervini, F.; De Leo, F. Prodution of active angiotensin-i converting enzyme inhibitory peptides derived from bovine β-casein by recombinant DNA technologies. Biotechnol. J.,  2007, 2(11), 1425-1434.
[http://dx.doi.org/10.1002/biot.200700092] 
[189] 
Liu, D.; Sun, H.; Zhang, L.; Li, S. High-level expression of milk-derived antihypertensive peptide in Escherichia coli and its bioactivity. J. Agric. Food Chem.,  2007, 55(13), 5109-5112.
[http://dx.doi.org/10.1021/jf0703248] 
[190] 
Rao, S.; Su, Y.; Li, J.; Xu, Z.; Yang, Y. Design and expression of recombinant antihypertensive peptide multimer gene in Escherichia coli bl21. J. Microbiol. Biotechnol.,  2009, 19(12), 1620-1627.
[http://dx.doi.org/10.4014/jmb.0905.05055] 
[191] 
Rao, S.; Xu, Z.; Su, Y.; Li, J.; Sun, J.; Yang, Y. Cloning, soluble expression, and production of recombinant antihypertensive peptide multimer (ahpm-2) in Escherichia coli for bioactivity identification. Protein Pept. Lett.,  2011, 18(7), 699-706.
[http://dx.doi.org/10.2174/092986611795446067] 
[192] 
Ames, B.N.; Shigenaga, M.K.; Hagen, T.M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA,  1993, 90(17), 7915-7922.
[http://dx.doi.org/10.1073/pnas.90.17.7915] 
[193] 
Bagchi, D.; Bagchi, M.; Stohs, S.J.; Das, D.K.; Ray, S.D.; Kuszynski, C.A.; Joshi, S.S.; Pruess, H.G. Free radicals and grape seed proanthocyanidin extract: Importance in human health and disease prevention. Toxicology,  2000, 148(2–3), 187-197.
[http://dx.doi.org/10.1016/S0300-483X(00)00210-9] 
[194] 
Phadungkit, M.; Somdee, T.; Kangsadalampai, K. Phytochemical screening, antioxidant and antimutagenic activities of selected thai edible plant extracts. J. Med. Plants Res.,  2012, 6(5), 662-666.
[http://dx.doi.org/10.5897/JMPR11.517] 
[195] 
Lin, K.; Yeh, H.; Lin, S.; Yang, C.; Tsai, S.; Tsai, J.; Chao, P-Y. Antioxidant activities of methanol extracts from selected Taiwanese herbaceous plants. J. Food Nutr. Res.,  2014, 2(8), 435-442.
[http://dx.doi.org/10.12691/jfnr-2-8-2] 
[196] 
Kahl, R.; Kappus, H. Toxicology of the synthetic antioxidants bha and bht in comparison with the natural antioxidant vitamin E. Zeitschrift fur Leb. Und-forsch.,  1993, 196(4), 329-338.
[197] 
Madsen, H.L.; Bertelsen, G. Spices as antioxidants. Trends Food Sci. Technol.,  1995, 6(8), 271-277.
[http://dx.doi.org/10.1016/S0924-2244(00)89112-8] 
[198] 
He, R.; Ju, X.; Yuan, J.; Wang, L.; Girgih, A.T.; Aluko, R.E. Antioxidant activities of rapeseed peptides produced by solid state fermentation. Food Res. Int.,  2012, 49(1), 432-438.
[http://dx.doi.org/10.1016/j.foodres.2012.08.023] 
[199] 
Wang, Y.; Chen, H.; Wang, J.; Xing, L. Preparation of active corn peptides from zein through double enzymes immobilized with calcium alginate-chitosan beads. Process Biochem.,  2014, 49(10), 1682-1690.
[http://dx.doi.org/10.1016/j.procbio.2014.07.002] 
[200] 
Torres-Fuentes, C.; del Mar Contreras, M.; Recio, I.; Alaiz, M.; Vioque, J. Identification and characterization of antioxidant peptides from chickpea protein hydrolysates. Food Chem.,  2015, 180, 194-202.
[http://dx.doi.org/10.1016/j.foodchem.2015.02.046] 
[201] 
Wichai, T.; Boonsombat, R. Bioactive activity of a recombinant longan (Dimocarpus longan lour.) seed peptide. Proc. Int. Conf. Appl. Sci. Health,  2018, pp. 40-46.
[202] 
Ahmadi-Vavsari, F.; Farmani, J.; Dehestani, A. Recombinant production of a bioactive peptide from spotless smooth-hound (Mustelus griseus) muscle and characterization of its antioxidant activity. Mol. Biol. Rep.,  2019, 46(3), 2599-2608.
[http://dx.doi.org/10.1007/s11033-018-4468-1] 
[203] 
Wu, Y.; Ma, Y.; Li, L.; Yang, X. Molecular modification, expression and purification of new subtype antioxidant peptide from Pinctada fucata by recombinant Escherichia coli to improve antioxidant-activity. J. Food Sci. Technol.,  2018, 55(10), 4266-4275.
[http://dx.doi.org/10.1007/s13197-018-3365-x] 
Cite As
Current Pharmaceutical Biotechnology

Recombinant Active Peptides and their Therapeutic Functions

Abstract

Graphical Abstract
