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中国生物工程杂志

China Biotechnology
China Biotechnology  2016, Vol. 36 Issue (8): 89-98    DOI: 10.13523/j.cb.20160812
    
Research Advances in the Design of Synthetic Antimicrobial Peptides with Enhanced Therapeutic Potentials
WEN Sai, LIU Huai-ran, HAN Xu, LI Tian, XING Xuan
School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing Higher Institution Engineering Research Center of Food Additives and Ingredients, Beijing Key Laboratory of Food Flavor Chemistry, Beijing 100048, China
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Abstract  

Natural antimicrobial peptides (AMPs) are small cationic peptides with potent and broad-spectrum antimicrobial activities which have received great attention as a promising antibiotic candidates to overcome the global epidemic of antibiotics-resistant infections. Natural AMPs has provided a wealth of information on the structure-activity relationship accounting for antimicrobial activity to design novel synthetic AMPs with improved protease-resistance, reduced cost of production and less hemolysis and toxicity, which greatly promotes the potential of synthetic peptides as anti-infectious agent. Firstly the general strategies and technologies employed in the design and optimization of synthetic peptides, i.e., chemical modification, protein engineering, in silico design and screening, and minimalist de novo design were summarized. Finally, the synthetic AMPs in clinical trail with outstanding therapeutic potentials and future perspectives of improved AMPs for therapeutic applications were highlighted.



Key wordsSynthetic antimicrobial peptide      Anti-infection      Molecular modification     
Received: 25 May 2016      Published: 25 August 2016
ZTFLH:  Q819  
Cite this article:

WEN Sai, LIU Huai-ran, HAN Xu, LI Tian, XING Xuan. Research Advances in the Design of Synthetic Antimicrobial Peptides with Enhanced Therapeutic Potentials. China Biotechnology, 2016, 36(8): 89-98.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.20160812     OR     https://manu60.magtech.com.cn/biotech/Y2016/V36/I8/89

[1] Wiesner J, Vilcinskas A. Antimicrobial peptides-the ancient arm of the human immune system. Virulence, 2010, 1(5):440-446.
[2] Melo M N, Ferre R, Castanho M A. Antimicrobial peptides:linking partition, activity and high membrane-bound concentrations. Nat Rev Microbiol, 2009, 7(3):245-250.
[3] Hancock R E, Sahl H G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol, 2006, 24(12):1551-1557.
[4] Lee T H, Hall K N, Aguilar M I. Antimicrobial peptide structure and mechanism of action:a focus on the role of membrane structure. Curr Top Med Chem, 2016, 16(1):25-39.
[5] Malmsten M. Antimicrobial peptides. Upsala Journal of Medical Sciences, 2014, 119:199-204.
[6] Nguyen L T, Haney E F, Vogel H J. The expanding scope of antimicrobial peptide structures and their modes of action. Trends in Biotechnology, 2011, 29(9):464-472.
[7] Jenssen H, Hamill P, Hancock R E W. Peptide antimicrobial agents. Clinical Microbiology Reviews, 2006, 19(3):491-511.
[8] Seo M D, Won H S, Kim J H, et al. Antimicrobial peptides for therapeutic applications:a review. Molecules, 2012, 17(10):12276-12286.
[9] Lee I H, Cho Y, Lehrer R I. Effects of pH and salinity on the antimicrobial properties of clavanins. Infection and Immunity, 1997, 65(7):2898-2903.
[10] Reddy K V, Yedery R D, Aranha C. Antimicrobial peptides:premises and promises. Int J Antimicrob Agents, 2004, 24(6):536-547.
[11] Str mstedt A A, Pasupuleti M, Schmidtchen A, et al. Evaluation of strategies for improving proteolytic resistance of antimicrobial peptides by using variants of EFK17, an internal segment of LL-37. Antimicrobial Agents and Chemotherapy, 2009, 53(2):593-602.
[12] Svendson J, Stensen W, Brandsdal B O. Antimicrobial peptides with stability toward tryptic degradation. Biochemistry 2008, 47(12):3777-3788.
[13] Nguyen L T, Chau J K, Perry N A, et al. Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. PLoS ONE, 2010, 5(9):e12684.
[14] Morris C J, Beck K, Fox M A, et al. Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery. Antimicrobial Agents and Chemotherapy, 2012, 56(6):3298-3308.
[15] Zhang G, Han B, Lin X, et al. Modification of antimicrobial peptide with low molar mass poly(ethylene glycol). Biochemistry, 2008, 144(6):781-788.
[16] Costa F, Carvalho I F, Montelaro R C, et al. Covalent immobilization of antimicrobial peptides (AMPs) onto biomaterial surfaces. Acta Biomaterialia, 2011, 7(4):1431-1440.
[17] Matthias G, Kamran N. Preparation of LL-37-grafted titanium surfaces with bactericidal activity. Bioconjugate Chemistry, 2006, 17(2):548-550.
[18] Dutta D, Kumar N, Willcox M. Antimicrobial activity of four cationic peptides immobilised to poly-hydroxyethylmethacrylate. Biofouling, 2016, 32(4):429-438.
[19] Humblot V, Yala J F, Thebault P, et al. The antibacterial activity of magainin I immobilized onto mixed thiols self-assembled monolayers. Biomaterials, 2009, 30(21):3503-3512.
[20] Glinel K, Jonas A M, Jouenne T, et al. Antibacterial and antifouling polymer brushes incorporating antimicrobial peptide. Bioconjug Chem, 2009, 20(1):71-77.
[21] Willcox M D, Hume E B, Aliwarga Y, et al. A novel cationic-peptide coating for the prevention of microbial colonization on contact lenses. J Appl Microbiol, 2008, 105(6):1817-1825.
[22] Chen R, Cole N, Willcox M D, et al. Synthesis, characterization and in vitro activity of a surface-attached antimicrobial cationic peptide. Biofouling, 2009, 25(6):517-524.
[23] Yazici H, O'Neill M B, Kacar T, et al. Engineered chimeric peptides as antimicrobial surface coating agents toward infection-free implants. ACS Appl Mater Interfaces, 2016, 8(8):5070-5081.
[24] Bagheri M, Beyermann M, Dathe M. Immobilization reduces the activity of surface-bound cationic antimicrobial peptides with no influence upon the activity spectrum. Antimicrob Agents Chemother, 2009, 53(3):1132-1141.
[25] Qi X, Poernomo G, Wang K, et al. Covalent immobilization of nisin on multi-walled carbon nanotubes:superior antimicrobial and anti-biofilm properties. Nanoscale, 2011, 3(4):1874-1880.
[26] Haynie S L, Crum G A, Doele B A. Antimicrobial activities of amphiphilic peptides covalently bonded to a water-insoluble resin. Antimicrobial Agents and Chemotherapy, 1995, 39(2):301-307.
[27] Cho W M, Joshi B P, Cho H, et al. Design and synthesis of novel antibacterial peptide-resin conjugates. Bioorg Med Chem Lett, 2007, 17(21):5772-5776.
[28] Easton D M, Nijnik A, Mayer M L, et al. Potential of immunomodulatory host defense peptides as novel anti-infectives. Trends Biotechnol, 2009, 27(10):582-590.
[29] Morrison G M, Rolfe M, Kilanowski F M, et al. Identification and characterization of a novel murine beta-defensin-related gene. Mamm Genome, 2002, 13(8):445-451.
[30] Schroeder B O, Wu Z, Nuding S, et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta-defensin 1. Nature, 2011, 469(7330):419-423.
[31] Lundy F T, Nelson J, Lockhart D, et al. Antimicrobial activity of truncated alpha-defensin (human neutrophil peptide (HNP)-1) analogues without disulphide bridges. Mol Immunol, 2008, 45(1):190-193.
[32] Zimmermann G R, Legault P, Selsted M E, et al. Solution structure of bovine neutrophil beta-defensin-12:the peptide fold of the beta-defensins is identical to that of the classical defensins. Biochemistry, 1995, 34(41):13663-13671.
[33] Park Y, Hahm K S. Novel short AMP:design and activity study. Protein Pept Lett, 2012, 19(6):652-656.
[34] Qu P, Gao W, Chen H, et al. The central hinge link truncation of the antimicrobial peptide fowlicidin-3 enhances its cell selectivity without antibacterial activity loss. Antimicrob Agents Chemother, 2016, 60(5):2798-2806.
[35] Zasloff M. Inducing endogenous antimicrobial peptides to battle infections. Proc Natl Acad Sci U S A, 2006, 103(24):8913-8914.
[36] Braunstein A, Papo N, Shai Y. In vitro activity and potency of an intravenously injected antimicrobial peptide and its DL amino acid analog in mice infected with bacteria. Antimicrob Agents Chemother, 2004, 48(8):3127-3129.
[37] Nan Y H, Bang J K, Jacob B, et al. Prokaryotic selectivity and LPS-neutralizing activity of short antimicrobial peptides designed from the human antimicrobial peptide LL-37. Peptides, 2012, 35(2):239-247.
[38] Molhoek E M, van Dijk A, Veldhuizen E J, et al. Improved proteolytic stability of chicken cathelicidin-2 derived peptides by D-amino acid substitutions and cyclization. Peptides, 2011, 32(5):875-880.
[39] Avitabile C, Capparelli R, Rigano M M, et al. Antimicrobial peptides from plants:stabilization of the gamma core of a tomato defensin by intramolecular disulfide bond. J Pept Sci, 2013, 19(4):240-245.
[40] Rozek A, Powers J P, Friedrich C L, et al. Structure-based design of an indolicidin peptide analogue with increased protease stability. Biochemistry, 2003, 42(48):14130-14138.
[41] Chan L Y, Zhang V M, Huang Y H, et al. Cyclization of the antimicrobial peptide gomesin with native chemical ligation:influences on stability and bioactivity. Chembiochem, 2013, 14(5):617-624.
[42] Unger T, Oren Z, Shai Y. The effect of cyclization of magainin 2 and melittin analogues on structure, function, and model membrane interactions:implication to their mode of action. Biochemistry, 2001, 40(21):6388-6397.
[43] Nguyen L T, Schibli D J, Vogel H J. Structural studies and model membrane interactions of two peptides derived from bovine lactoferricin. J Pept Sci, 2005, 11(7):379-389.
[44] Eckert R, He J, Yarbrough D K, et al. Targeted killing of Streptococcus mutans by a pheromone-guided "Smart" antimicrobial peptide. Antimicrobial Agents and Chemotherapy, 2006, 50(11):3651-3657.
[45] He J, Anderson M H, Shi W, et al. Design and activity of a ‘dual-targeted’ antimicrobial peptide. International Journal of Antimicrobial Agents, 2009, 33(6):532-537.
[46] An L L, Yang Y H, Ma X T, et al. LL-37 enhances adaptive antitumor immune response in a murine model when genetically fused with M-CSFR(J6-1) DNA vaccine. Leukemia Research, 2005, 29(5):535-543.
[47] Che Y Z, Li Y R, Zou H S, et al. A novel antimicrobial protein for plant protection consisting of a Xanthomonas oryzae harpin and active domains of cecropin A and melittin. Microb Biotechnol, 2011, 4(6):777-793.
[48] Frecer V, Ho B, Ding J L. De novo design of potent antimicrobial peptides. Antimicrob Agents Chemother, 2004, 48(9):3349-3357.
[49] Bhattacharjya S, Domadia P N, Bhunia A, et al. High-resolution solution structure of a designed peptide bound to lipopolysaccharide:transferred nuclear overhauser effects, micelle selectivity, and anti-endotoxic activity. Biochemistry, 2007, 46(20):5864-5874.
[50] Bhattacharjya S. De novo designed lipopolysaccharide binding peptides:structure based development of antiendotoxic and antimicrobial drugs. Curr Med Chem, 2010, 17(27):3080-3093.
[51] Zakeri B, Lu T K. Synthetic biology of antimicrobial discovery. ACS Synth Biol, 2013, 2(7):358-372.
[52] 刘黎. 抗菌肽活性的力学调控机制研究. 广州:华南理工大学, 2012. Liu L. The mechanical mechanism to regulate antimicrobial activity of antimicrobial peptides. Guangzhou:South China University of Technology, 2012.
[53] Cherkasov A, Hilpert K, Jenssen H, et al. Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs. ACS Chem Biol, 2009, 4(1):65-74.
[54] Fjell C D, Jenssen H, Hilpert K, et al. Identification of novel antibacterial peptides by chemoinformatics and machine learning. J Med Chem, 2009, 52(7):2006-2015.
[55] Fjell C D, Jenssen H, Cheung W A, et al. Optimization of antibacterial peptides by genetic algorithms and cheminformatics. Chem Biol Drug Des, 2011, 77(1):48-56.
[56] Strom M B, Haug B E, Skar M L, et al. The pharmacophore of short cationic antibacterial peptides. J Med Chem, 2003, 46(9):1567-1570.
[57] Liu Z, Brady A, Young A, et al. Length effects in antimicrobial peptides of the (RW)n series. Antimicrob Agents Chemother, 2007, 51(2):597-603.
[58] Deslouches B, Steckbeck J D, Craigo J K, et al. Rational design of engineered cationic antimicrobial peptides consisting exclusively of arginine and tryptophan, and their activity against multidrug-resistant pathogens. Antimicrob Agents Chemother, 2013, 57(6):2511-2521.
[59] Chan D I, Prenner E J, Vogel H J. Tryptophan- and arginine-rich antimicrobial peptides:structures and mechanisms of action. Biochim Biophys Acta, 2006, 9(202):21.
[60] Wiradharma N, Khoe U, Hauser C A, et al. Synthetic cationic amphiphilic alpha-helical peptides as antimicrobial agents. Biomaterials, 2011, 32(8):2204-2212.
[61] Wiradharma N, Khan M, Yong L K, et al. The effect of thiol functional group incorporation into cationic helical peptides on antimicrobial activities and spectra. Biomaterials, 2011, 32(34):9100-9108.
[62] Wiradharma N, Sng M Y, Khan M, et al. Rationally designed alpha-helical broad-spectrum antimicrobial peptides with idealized facial amphiphilicity. Macromol Rapid Commun, 2013, 34(1):74-80.
[63] Javadpour M M, Juban M M, Lo W C, et al. De novo antimicrobial peptides with low mammalian cell toxicity. J Med Chem, 1996, 39(16):3107-3113.
[64] Deslouches B, Phadke S M, Lazarevic V, et al. De novo generation of cationic antimicrobial peptides:influence of length and tryptophan substitution on antimicrobial activity. Antimicrob Agents Chemother, 2005, 49(1):316-322.
[65] Kang S J, Won H S, Choi W S, et al. De novo generation of antimicrobial LK peptides with a single tryptophan at the critical amphipathic interface. J Pept Sci, 2009, 15(9):583-588.
[66] Jiang Z, Vasil A I, Gera L, et al. Rational design of alpha-helical antimicrobial peptides to target Gram-negative pathogens, Acinetobacter baumannii and Pseudomonas aeruginosa:utilization of charge, ‘specificity determinants’, total hydrophobicity, hydrophobe type and location as design parameters to improve the therapeutic ratio. Chem Biol Drug Des, 2011, 77(4):225-240.
[67] Wu H, Ong Z Y, Liu S, et al. Synthetic β-sheet forming peptide amphiphiles for treatment of fungal keratitis. Biomaterials, 2015, 43:44-49.
[68] Ong Z Y, Gao S J, Yang Y Y. Short synthetic β-sheet forming peptide amphiphiles as broad spectrum antimicrobials with antibiofilm and endotoxin neutralizing capabilities. Advanced Functional Materials, 2013, 23(29):3682-3692.
[69] Ong Z Y, Cheng J, Huang Y, et al. Effect of stereochemistry, chain length and sequence pattern on antimicrobial properties of short synthetic beta-sheet forming peptide amphiphiles. Biomaterials, 2014, 35(4):1315-1325.
[70] Murugan R N, Jacob B, Kim E H, et al. Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents. Bioorg Med Chem Lett, 2013, 23(16):4633-4636.
[71] Haisma E M, de Breij A, Chan H, et al. LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin equivalents. Antimicrob Agents Chemother, 2014, 58(8):4411-4419.
[72] Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev, 2010, 74(3):417-433.
[73] Tan S, Gan C, Li R, et al. A novel chemosynthetic peptide with beta-sheet motif efficiently kills Klebsiella pneumoniae in a mouse model. Int J Nanomedicine, 2015, 10:1045-1059.
[74] Brouwer C P, Rahman M, Welling M M. Discovery and development of a synthetic peptide derived from lactoferrin for clinical use. Peptides, 2011, 32(9):1953-1963.
[75] Lupetti A, Paulusma-Annema A, Welling M M, et al. Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species. Antimicrob Agents Chemother, 2003, 47(1):262-267.
[76] Rothstein D M, Spacciapoli P, Tran L T, et al. Anticandida activity is retained in P-113, a 12-amino-acid fragment of histatin 5. Antimicrob Agents Chemother, 2001, 45(5):1367-1373.
[77] Zhang L, Parente J, Harris S M, et al. Antimicrobial peptide therapeutics for cystic fibrosis. Antimicrob Agents Chemother, 2005, 49(7):2921-2927.
[78] Ge Y, MacDonald D L, Holroyd K J, et al. In vitro antibacterial properties of pexiganan, an analog of magainin. Antimicrob Agents Chemother, 1999, 43(4):782-788.
[79] Fritsche T R, Rhomberg P R, Sader H S, et al. Antimicrobial activity of omiganan pentahydrochloride against contemporary fungal pathogens responsible for catheter-associated infections. Antimicrob Agents Chemother, 2008, 52(3):1187-1189.
[80] Domingues M M, Santos N C, Castanho M A. Antimicrobial peptide rBPI21:a translational overview from bench to clinical studies. Curr Protein Pept Sci, 2012, 13(7):611-619.
[81] Dutta P, Das S. Mammalian antimicrobial peptides:promising therapeutic targets against infection and chronic inflammation. Curr Top Med Chem, 2016, 16(1):99-129.

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