Scientific Online Resource System

Scripta Scientifica Medica

Review on the pharmacological activities of lactoferricin and lactoferricin analogues

Dimana Dimitrova, Antonia Hristova, Momchil Lambev, Silvia Mihaylova, Tamara Paipanova, Stefka Valcheva-Kuzmanova

Abstract

INTRODUCTION: Antimicrobial peptides (AMPs) are a growing class of natural and synthetic compounds with a wide spectrum of targets including viruses, bacteria, fungi, and parasites.

AIM: The aim of the present review was to make an overview of the available literature on the pharmacological activities of these peptides, focusing on lactoferricin and lactoferricin analogues.

MATERIALS AND METHODS: To achieve this aim, information from databases, such as PubMed, Google Scholar and ResearchGate was searched and summarized.

RESULTS: Antimicrobial peptides (AMPs) are considered a promising alternative to the antibiotics used nowadays. They have drawn a special attention in the fight against infections caused by antibiotic-resistant bacterial strains. Lactoferricin is the most studied AMP derived from milk protein. Lactoferricin (Lfcin) is a fragment of the ferro-chelate complex of the bovine protein lactoferrin (Lf). The amphipathic and cationic properties of Lfcin account for its broad spectrum antimicrobial activity. Lfcin also manifests potential antiviral, immunomodulatory, antitumor and anti-inflammatory properties. Shorter analogues of Lfcins have been synthesized with a broad spectrum of activities and enhanced pharmacokinetic properties.

CONCLUSION: Lactoferricin and its analogues are a good demonstration that it is possible to design and obtain synthetic peptides with enhanced pharmacological activities.


Keywords

antimicrobial peptides; lactoferricin; lactoferricin activities; lactoferricin analogues

Full Text


References

World Health Organization. Antimicrobial Resistance: Global Report on Surveillance; World Health Organization: Geneva, Switzerland, 2014.

León-Calvijo MA, Leal-Castro AL, Almanzar-Reina GA, Rosas-Pérez JE, García-Castañeda JE, Rivera-Monroy ZJ. Antibacterial activity of synthetic peptides derived from lactoferricin against Escherichia coli ATCC 25922 and Enterococcus faecalis ATCC 29212. Biomed Res Int. 2015;2015:453826. doi: 10.1155/2015/453826.

Reddy KV, Yedery RD, Aranha C. Antimicrobial peptides: premises and promises. Int J Antimicrob Agents 2004;24(6):536-47. doi: 10.1016/j.ijantimicag.2004.09.005.

Hancock RE. Peptide antibiotics. Lancet. 1997;349(9049):418-22. doi: 10.1016/S0140-6736(97)80051-7.

Powers JP, Hancock RE. The relationship between peptide structure and antibacterial activity. Peptides. 2003;24(11):1681-91. doi: 10.1016/j.peptides.2003.08.023.

Kragol G, Hoffmann R, Chattergoon MA, Lovas S, Cudic M, Bulet P, et al. Identification of crucial residues for the antibacterial activity of the proline-rich peptide, pyrrhocoricin. Eur J Biochem. 2002;269(17):4226-37. doi: 10.1046/j.1432-1033.2002.03119.x.

Chan DI, Prenner EJ, Vogel HJ. Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action. Biochim Biophys Acta. 2006;1758(9):1184-202. doi: 10.1016/j.bbamem.2006.04.006.

Dong N, Ma Q, Shan A, Lv Y, Hu W, Gu Y, et al. Strand length-dependent antimicrobial activity and membrane-active mechanism of arginine- and valine-rich β-hairpin-like antimicrobial peptides. Antimicrob Agents Chemother. 2012;56(6):2994-3003. doi: 10.1128/AAC.06327-11.

Baumann T, Kämpfer U, Schürch S, Schaller J, Largiadèr C, Nentwig W, et al. Antimicrobial glycine-rich peptides from the hemocytes of the spider Cupiennius salei. Cell Mol Life Sci. 2010;67(16):2787-98. doi: 10.1007/s00018-010-0364-0.

Ilić N, Novković M, Guida F, Xhindoli D, Benincasa M, Tossi A, et al. Selective antimicrobial activity and mode of action of adepantins, glycine-rich peptide antibiotics based on anuran antimicrobial peptide sequences. Biochim Biophys Acta. 2013;1828(3):1004-12. doi: 10.1016/j.bbamem.2012.11.017.

Selsted ME, Brown DM, DeLange RJ, Harwig SS, Lehrer RI. Primary structures of six antimicrobial peptides of rabbit peritoneal neutrophils. J Biol Chem. 1985;260(8):4579-84.

Oppenheim FG, Xu T, McMillian FM, Levitz SM, Diamond RD, Offner GD, et al. Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. J Biol Chem. 1988;263(16):7472-7.

Rebecca LA, Nadin MS, Enzo AP, Mrinal B. Tryptophan-rich antimicrobial peptides: properties and applications. In: Méndez-Vilas A, editor. Microbial pathogens and strategies for combating them: science, technology and education. Formatex Research Center; 2013. p. 1395-1405.

Tomita M, Wakabayashi H, Shin K, Yamauchi K, Yaeshima T, Iwatsuki K. Twenty-five years of research on bovine lactoferrin applications. Biochimie. 2009;91(1):52-7. doi: 10.1016/j.biochi.2008.05.021.

Vorland LH, Ulvatne H, Andersen J, Haukland H, Rekdal O, Svendsen JS, et al. Lactoferricin of bovine origin is more active than lactoferricins of human, murine and caprine origin. Scand J Infect Dis. 1998;30(5):513-7. doi: 10.1080/00365549850161557.

Hwang PM, Zhou N, Shan X, Arrowsmith CH, Vogel HJ. Three-dimensional solution structure of lactoferricin B, an antimicrobial peptide derived from bovine lactoferrin. Biochemistry. 1998;37(12):4288-98. doi: 10.1021/bi972323m.

Chen R, Cole N, Dutta D, Kumar N, Willcox MDP. Antimicrobial activity of immobilized lactoferrin and lactoferricin. J Biomed Mater Res B Appl Biomater. 2017;105(8):2612-7. doi: 10.1002/jbm.b.33804.

Hoek KS, Milne JM, Grieve PA, Dionysius Dam, Smith R. Antibacterial activity in bovine lactoferrin-derived peptides. Antimicrob Agents Chemother. 1997;41(1):54-9.

Tomita M, Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K. Potent antibacterial peptides generated by pepsin digestion of bovine lactoferrin. J Dairy Sci. 1991;74(12):4137-42. doi: 10.3168/jds.S0022-0302(91)78608-6.

Saito H, Miyakawa H, Tamura Y, Shimamura S, Tomita M. Potent bactericidal activity of bovine lactoferrin hydrolysate produced by heat treatment at acidic pH. J Dairy Sci. 1991;74(11):3724-30. doi: 10.3168/jds.S0022-0302(91)78563-9.

Hao Y, Yang N, Teng D, Wang X, Mao R, Wang J. A review of the design and modification of lactoferricins and their derivatives. BioMetals. 2018;31(2):1-11. doi: 10.1007/s10534-018-0086-6.

Jenssen H. Anti herpes simplex virus activity of lactoferrin/lactoferricin – an example of antiviral activity of antimicrobial protein/peptide. Cell Mol Life Sci. 2005;62(24):3002-13. doi: 10.1007/s00018-005-5228-7.

Andersen JH, Jenssen H, Sandvik K, Gutteberg TJ. Anti-HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface. J Med Virol. 2004;74(2):262-71. doi: 10.1002/jmv.20171.

Jenssen H, Andersen JH, Uhlin-Hansen L, Gutteberg TJ, Rekdal Ø. Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate. Antiviral Res. 2004;61(2):101-9. doi: 10.1016/j.antiviral.2003.09.001.

Andersen JH, Jenssen H, Gutteberg TJ. Lactoferrin and lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit synergy when combined with acyclovir. Antiviral Res. 2003;58(3):209-15. doi: 10.1016/s0166-3542(02)00214-0.

Shestakov A, Jenssen H, Nordstrom I, Eriksson K. Lactoferricin but not lactoferrin inhibit herpes simplex virus type 2 infection in mice. Antiviral Res. 2012;93(3):340-5. doi: 10.1016/j.antiviral.2012.01.003.

Mistry N, Drobni P, Naslund J, Sunkari VG, Jenssen H, Evander M. The anti-papillomavirus activity of human and bovine lactoferricin. Antiviral Res. 2007;75(3):258-65. doi: 10.1016/j.antiviral.2007.03.012.

Berkhout B, van Wamel JL, Beljaars L, Meijer DK, Visser S, Floris R. Characterization of the anti-HIV effects of native lactoferrin and other milk proteins and proteinderived peptides. Antiviral Res. 2002;55(2):341-55. doi: 10.1016/s0166-3542(02)00069-4.

Riedl S, Rinner B, Tumer S, Schaider H, Lohner K, Zweytick D. Targeting the cancer cell membrane specifically with human lactoferricin derivatives. Ann Oncol. 2011;22(suppl. 3):iii31-iii34.

Pan WR, Chen PW, Chen YL, Hsu HC, Lin CC, Chen WJ. Bovine lactoferricin B induces apoptosis of human gastric cancer cell line AGS by inhibition of autophagy at a late stage. J Dairy Sci. 2013;96(12):7511-20. doi: 10.3168/jds.2013-7285.

Jiang R, Lönnerdal B. Bovine lactoferrin and lactoferricin exert antitumor activities on human colorectal cancer cells (HT-29) by activating various signaling pathways. Biochem Cell Biol. 2017;95(1):99-109. doi: 10.1139/bcb-2016-0094.

Shigeru T, Michiko Y, Yoshiko Y, Yasuko K, Tasuke K, Keiya T. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). IJC. 1980;26(2):171-6. doi:10.1002/ijc.2910260208.

Yoo YC, Watanabe R, Koike Y, Mitobe M, Shimazaki K, Watanabe S, et al. Apoptosis in human leukemic cells induced by lactoferricin, a bovine milk proteinderived peptide: involvement of reactive oxygen species. Biochem Biophys Res Commun. 1997;237(3):624-8. doi: 10.1006/bbrc.1997.7199.

Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma. Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res. 1997;88(2):184-90. doi: 10.1111/j.1349-7006.1997.tb00364.x.

Khan AR, Taneja P. Cationic peptide lactoferricin B inhibits glutathione s-transferase P1 from human placenta and breast cancer cell line MDA-MB-231 preventing anticancer drug metabolism. Int J Pharm Pharma Sci. 2015;7:238-41.

Malone A. Impact of species-specific lactoferricin peptides on macrophage-associated inflammatory responses. Master Thesis. Dalhousie University Halifax, Nova Scotia, 2015.

Kanyshkova TG, Buneva VN, Nevinsky GA. Lactoferrin and host defence: an overview of its immuno-modulating and anti-inflammatory properties. Biometals 2004;66(1):1-7.

Kruzel ML, Actor JK, Radak Z, Bacsi A, Saavedra-Molina A, Boldogh I, et al. Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model. Innate Immun. 2010;16(2):67-79. doi: 10.1177/1753425909105317.

Kruzel ML, Harari Y, Mailman D, Actor JK, Zimecki M. Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice. Clin Exp Immunol. 2002;130(1):25-31. doi: 10.1046/j.1365-2249.2002.01956.x.

Håversen LA, Baltzer L, Dolphin G, Hanson LA, Mattsby-Baltzer I. Anti-inflammatory activities of human lactoferrin in acute dextran sulphate-induced colitis in mice. Scand J Immunol. 2003;57(1):2-10. doi: 10.1046/j.1365-3083.2003.01162.x.

Yan D, Kc R, Chen D, Xiao G, Im HJ. Bovine lactoferricin-induced anti-inflammation is, in part, via up-regulation of interleukin-11 by secondary activation of STAT3 in human articular cartilage. J Biol Chem. 2013;288(44):31655-69. doi: 10.1074/jbc.M112.440420.

van der Does AM, Bogaards SJ, Ravensbergen B, Beekhuizen H, van Dissel JT, Nibbering PH. Antimicrobial peptide hLF1-11 directs granulocytemacrophage colony-stimulating factor-driven monocyte differentiation toward macrophages with enhanced recognition and clearance of pathogens. Antimicrob Agents Chemother. 2010;54(2):811-6. doi: 10.1128/AAC.00652-09.

Zhang GH, Mann DM, Tsai CM. Neutralization of endotoxin in vitro and in vivo by a human lactoferrin-derived peptide. Infect Immun. 1999;67(3):1353-8.

van der Does AM, Hensbergen PJ, Bogaards SJ, Cansoy M, Deelder AM, van Leeuwen HC, et al. The human lactoferrin-derived peptide hLF1-11 exerts immunomodulatory effects by specific inhibition of myeloperoxidase activity. J Immunol. 2012;188(10):5012-9. doi: 10.4049/jimmunol.1102777.

Kuppusamy R, Willcox M, Black D, Kumar N. Short cationic peptidomimetic antimicrobials. Antibiotics (Basel). 2019;8(2): pii: E44. doi:10.3390/antibiotics8020044.

Laverty G, Gorman SP, Gilmore BF. The potential of antimicrobial peptides as biocides. Int J Mol Sci. 2011;12(10):6566-96. doi:10.3390/ijms12106566.

Chaparro S, Salguero J, Baquero D, Pérez J. Effect of polyvalence on the antibacterial activity of a synthetic peptide derived from bovine lactoferricin against healthcare-associated infectious pathogens. BioMed Res Int. 2018;6:1-12. doi:10.1155/2018/5252891.

Sun C, Li Y, Cao S, Wang H, Jiang C, Pang S, et al. Antibacterial activity and mechanism of action of bovine lactoferricin derivatives with symmetrical amino acid sequences. Int J Mol Sci. 2018;19(10):2951. doi: 10.3390/ijms19102951.




DOI: http://dx.doi.org/10.14748/ssm.v51i1.5887

Refbacks

About The Authors

Dimana Dimitrova
Medical University of Varna
Bulgaria

Educational Sector Assistant Pharmacist, Medical College

Antonia Hristova
Medical University of Varna

Educational Sector Assistant Pharmacist, Medical College

Momchil Lambev
Medical University of Varna
Bulgaria

Educational Sector Assistant Pharmacist, Medical College

Silvia Mihaylova
Medical University of Varna
Bulgaria

Educational Sector Assistant Pharmacist, Medical College

Tamara Paipanova
Institute of Molecular Biology Acad. Roumen Tsanev, Bulgarian Academy of Sciences, Sofia
Bulgaria

Stefka Valcheva-Kuzmanova
Medical University of Varna
Bulgaria

Department of Pharmacology and Clinical Pharmacology and Therapeutics, Faculty of Medicine

Font Size


|