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Natural and synthetic peptides with antifungal activity

    Tecla Ciociola

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    ,
    Laura Giovati

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    ,
    Stefania Conti

    *Author for correspondence:

    E-mail Address: stefania.conti@unipr.it

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    ,
    Walter Magliani

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    ,
    Claudia Santinoli

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    &
    Luciano Polonelli

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Unit of Microbiology & Virology, Department of Biomedical, Biotechnological & Translational Sciences (S.Bi.Bi.T.), University of Parma, via Volturno 39, 43125 Parma, Italy

    Published Online:https://doi.org/10.4155/fmc-2016-0035

    In recent years, the increase of invasive fungal infections and the emergence of antifungal resistance stressed the need for new antifungal drugs. Peptides have shown to be good candidates for the development of alternative antimicrobial agents through high-throughput screening, and subsequent optimization according to a rational approach. This review presents a brief overview on antifungal natural peptides of different sources (animals, plants, micro-organisms), peptide fragments derived by proteolytic cleavage of precursor physiological proteins (cryptides), synthetic unnatural peptides and peptide derivatives. Antifungal peptides are schematically reported based on their structure, antifungal spectrum and reported effects. Natural or synthetic peptides and their modified derivatives may represent the basis for new compounds active against fungal infections.

    Papers of special note have been highlighted as: • of interest

    References

    • 1 Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci. Transl. Med. 4(165), 165rv113 (2012).
    • 2 Denning DW, Bromley MJ. How to bolster the antifungal pipeline. Science 347(6229), 1414–1416 (2015).
    • 3 Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov. Today 20(1), 122–128 (2015).
    • 4 Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov. Today 15(1–2), 40–56 (2010).
    • 5 Balkovec JM, Hughes DL, Masurekar PS, Sable CA, Schwartz RE, Singh SB. Discovery and development of first in class antifungal caspofungin (CANCIDAS(R)) – a case study. Nat. Prod. Rep. 31(1), 15–34 (2014).
    • 6 Pappas PG, Kauffman CA, Andes DR et al. Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 62(4), 409–417 (2016).
    • 7 Cruz J, Ortiz C, Guzman F, Fernandez-Lafuente R, Torres R. Antimicrobial peptides: promising compounds against pathogenic microorganisms. Curr. Med. Chem. 21(20), 2299–2321 (2014). • Updated and comprehensive review on antimicrobial peptides (AMPs), their current pharmacological development and potential therapeutic applications.
    • 8 Wei G-X, Campagna AN, Bobek LA. Factors affecting antimicrobial activity of MUC7 12-mer, a human salivary mucin-derived peptide. Ann. Clin. Microbiol. Antimicrob. 6(1), 1–10 (2007).
    • 9 Lombardi L, Maisetta G, Batoni G, Tavanti A. Insights into the antimicrobial properties of hepcidins: advantages and drawbacks as potential therapeutic agents. Molecules 20(4), 6319–6341 (2015).
    • 10 Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3(3), 238–250 (2005).
    • 11 Tam JP, Wang S, Wong KH, Tan WL. Antimicrobial peptides from plants. Pharmaceuticals 8(4), 711–757 (2015).
    • 12 Vriens K, Cammue BP, Thevissen K. Antifungal plant defensins: mechanisms of action and production. Molecules 19(8), 12280–12303 (2014).
    • 13 Anselmi M, Eliseo T, Zanetti-Polzi L et al. Structure of the lipodepsipeptide syringomycin E in phospholipids and sodium dodecylsulphate micelle studied by circular dichroism, NMR spectroscopy and molecular dynamics. BBA Biomembranes 1808(9), 2102–2110 (2011).
    • 14 Hegedüs N, Marx F. Antifungal proteins: more than antimicrobials? Fungal Biol. Rev. 26(4), 132–145 (2013).
    • 15 van der Weerden NL, Bleackley MR, Anderson MA. Properties and mechanisms of action of naturally occurring antifungal peptides. Cell. Mol. Life Sci. 70(19), 3545–3570 (2013). • Extensive and in-depth review on natural occurring antifungal peptides from diverse sources, outlining their complex mechanism of action.
    • 16 De Brucker K, Cammue BP, Thevissen K. Apoptosis-inducing antifungal peptides and proteins. Biochem. Soc. Trans. 39(5), 1527–1532 (2011).
    • 17 Nett JE. The host's reply to Candida biofilm. Pathogens 5(1), pii: E33 (2016).
    • 18 Ramage G, Rajendran R, Sherry L, Williams C. Fungal biofilm resistance. Int. J. Microbiol. 2012, 528521 (2012).
    • 19 Silva PM, Gonçalves S, Santos NC. Defensins: antifungal lessons from eukaryotes. Front. Microbiol. 5, 97 (2014).
    • 20 Shishido T, Humisto A, Jokela J et al. Antifungal compounds from Cyanobacteria. Mar. Drugs 13(4), 2124 (2015).
    • 21 Faruck MO, Yusof F, Chowdhury S. An overview of antifungal peptides derived from insect. Peptides 80, 80–88 (2016).
    • 22 Kang HK, Seo CH, Park Y. Marine peptides and their anti-infective activities. Mar. Drugs 13(1), 618–654 (2015).
    • 23 Wang G, Li X, Wang Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 44(D1), D1087–1093 (2016).
    • 24 Di Luca M, Maccari G, Maisetta G, Batoni G. BaAMPs: the database of biofilm-active antimicrobial peptides. Biofouling 31(2), 193–199 (2015).
    • 25 Duncan VMS, O'Neil DA. Commercialization of antifungal peptides. Fungal Biol. Rev. 26(4), 156–165 (2013).
    • 26 Hwang B, Hwang J-S, Lee J et al. Induction of yeast apoptosis by an antimicrobial peptide, Papiliocin. Biochem. Biophys. Res. Commun. 408(1), 89–93 (2011).
    • 27 Wang K, Jia F, Dang W et al. Antifungal effect and action mechanism of antimicrobial peptide polybia-CP. J. Pept. Sci. 22(1), 28–35 (2016).
    • 28 Wang K, Dang W, Xie J et al. Antimicrobial peptide protonectin disturbs the membrane integrity and induces ROS production in yeast cells. BBA Biomembranes 1848(10, Part A), 2365–2373 (2015).
    • 29 Choi H, Hwang J-S, Lee DG. Antifungal effect and pore-forming action of lactoferricin B like peptide derived from centipede Scolopendra subspinipes mutilans. BBA Biomembranes 1828(11), 2745–2750 (2013).
    • 30 Cho J, Lee DG. The antimicrobial peptide arenicin-1 promotes generation of reactive oxygen species and induction of apoptosis. BBA General Subjects 1810(12), 1246–1251 (2011).
    • 31 Landon C, Barbault F, Legrain M et al. Lead optimization of antifungal peptides with 3D NMR structures analysis. Protein Sci. 13(3), 703–713 (2004).
    • 32 Vizioli J, Bulet P, Hoffmann JA, Kafatos FC, Muller HM, Dimopoulos G. Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae. Proc. Natl Acad. Sci. USA 98(22), 12630–12635 (2001).
    • 33 Liu Z, Yuan K, Zhang R et al. Cloning and purification of the first termicin-like peptide from the cockroach Eupolyphaga sinensis. J. Venom. Anim. Toxins Incl. Trop. Dis. 22, 5 (2016).
    • 34 Youssef DT, Shaala LA, Mohamed GA, Badr JM, Bamanie FH, Ibrahim SR. Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei. Mar. Drugs 12(4), 1911–1923 (2014).
    • 35 Mangoni ML, Grazia AD, Cappiello F, Casciaro B, Luca V. Naturally occurring peptides from Rana temporaria: antimicrobial properties and more. Curr. Top. Med. Chem. 16(1), 54–64 (2016).
    • 36 Savelyeva A, Ghavami S, Davoodpour P, Asoodeh A, Los MJ. An overview of Brevinin superfamily: structure, function and clinical perspectives. Adv. Exp. Med. Biol. 818, 197–212 (2014).
    • 37 Matejuk A, Leng Q, Begum MD et al. Peptide-based antifungal therapies against emerging infections. Drugs Future 35(3), 197 (2010).
    • 38 Benincasa M, Scocchi M, Pacor S et al. Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts. J. Antimicrob. Chemother. 58(5), 950–959 (2006).
    • 39 Scarsini M, Tomasinsig L, Arzese A, D'Este F, Oro D, Skerlavaj B. Antifungal activity of cathelicidin peptides against planktonic and biofilm cultures of Candida species isolated from vaginal infections. Peptides 71, 211–221 (2015).
    • 40 Yu H, Liu X, Wang C et al. Assessing the potential of four cathelicidins for the management of mouse candidiasis and Candida albicans biofilms. Biochimie 121, 268–277 (2016).
    • 41 Raj PA, Marcus E, Edgerton M. Delineation of an active fragment and poly(l-proline) II conformation for candidacidal activity of Bactenecin 5. Biochemistry (Mosc.) 35(14), 4314–4325 (1996).
    • 42 Cabras T, Longhi R, Secundo F et al. Structural and functional characterization of the porcine proline-rich antifungal peptide SP-B isolated from salivary gland granules. J. Pept. Sci. 14(3), 251–260 (2008).
    • 43 Conti S, Radicioni G, Ciociola T et al. Structural and functional studies on a proline-rich peptide isolated from swine saliva endowed with antifungal activity towards Cryptococcus neoformans. BBA Biomembranes 1828(3), 1066–1074 (2013).
    • 44 Rao AG, Rood T, Maddox J, Duvick J. Synthesis and characterization of defensin NP-1. Int. J. Pept. Protein Res. 40(6), 507–514 (1992).
    • 45 Yamane ES, Bizerra FC, Oliveira EB et al. Unraveling the antifungal activity of a South American rattlesnake toxin crotamine. Biochimie 95(2), 231–240 (2013).
    • 46 Puri S, Edgerton M. How does it kill? Understanding the candidacidal mechanism of salivary Histatin 5. Eukaryot. Cell 13(8), 958–964 (2014).
    • 47 Swidergall M, Ernst JF. Interplay between Candida albicans and the antimicrobial peptide armory. Eukaryot. Cell 13(8), 950–957 (2014).
    • 48 Del Gaudio G, Lombardi L, Maisetta G et al. Antifungal activity of the noncytotoxic human peptide Hepcidin 20 against fluconazole-resistant Candida glabrata in human vaginal fluid. Antimicrob. Agents Chemother. 57(9), 4314–4321 (2013).
    • 49 Vriens K, Cools TL, Harvey PJ et al. The radish defensins RsAFP1 and RsAFP2 act synergistically with caspofungin against Candida albicans biofilms. Peptides 75, 71–79 (2016).
    • 50 Boldbaatar D, Gunasekera S, El-Seedi HR, Göransson U. Synthesis, structural characterization, and bioactivity of the stable peptide RCB-1 from Ricinus communis. J. Nat. Prod. 78(11), 2545–2551 (2015).
    • 51 Mith O, Benhamdi A, Castillo T et al. The antifungal plant defensin AhPDF1.1b is a beneficial factor involved in adaptive response to zinc overload when it is expressed in yeast cells. MicrobiologyOpen 4(3), 409–422 (2015).
    • 52 Vriens K, Cools TL, Harvey PJ et al. Synergistic activity of the plant defensin HsAFP1 and caspofungin against Candida albicans biofilms and planktonic cultures. PLoS ONE 10(8), e0132701 (2015).
    • 53 Hayes BME, Bleackley MR, Wiltshire JL, Anderson MA, Traven A, van der Weerden NL. Identification and mechanism of action of the plant defensin NaD1 as a new member of the antifungal drug arsenal against Candida albicans. Antimicrob. Agents Chemother. 57(8), 3667–3675 (2013).
    • 54 Ji H, Gheysen G, Ullah C et al. The role of thionins in rice defence against root pathogens. Mol. Plant Pathol. 16(8), 870–881 (2015).
    • 55 Wong JH, Ng TB. Sesquin a potent defensin-like antimicrobial peptide from ground beans with inhibitory activities toward tumor cells and HIV-1 reverse transcriptase. Peptides 26(7), 1120–1126 (2005).
    • 56 Nolde SB, Vassilevski AA, Rogozhin EA et al. Disulfide-stabilized helical hairpin structure and activity of a novel antifungal peptide EcAMP1 from seeds of barnyard grass (Echinochloa crus-galli). J. Biol. Chem. 286(28), 25145–25153 (2011).
    • 57 Slavokhotova AA, Rogozhin EA, Musolyamov AK et al. Novel antifungal alpha-hairpinin peptide from Stellaria media seeds: structure, biosynthesis, gene structure and evolution. Plant Mol. Biol. 84(1–2), 189–202 (2014).
    • 58 Harris PW, Yang SH, Molina A, Lopez G, Middleditch M, Brimble MA. Plant antimicrobial peptides snakin-1 and snakin-2: chemical synthesis and insights into the disulfide connectivity. Chemistry 20(17), 5102–5110 (2014).
    • 59 Mandal SM, Migliolo L, Franco OL, Ghosh AK. Identification of an antifungal peptide from Trapa natans fruits with inhibitory effects on Candida tropicalis biofilm formation. Peptides 32(8), 1741–1747 (2011).
    • 60 Delattin N, De Brucker K, Craik DJ et al. Plant-derived decapeptide OSIP108 interferes with Candida albicans biofilm formation without affecting cell viability. Antimicrob. Agents Chemother. 58(5), 2647–2656 (2014).
    • 61 Astafieva AA, Enyenihi AA, Rogozhin EA et al. Novel proline-hydroxyproline glycopeptides from the dandelion (Taraxacum officinale Wigg.) flowers: de novo sequencing and biological activity. Plant Sci. 238, 323–329 (2015).
    • 62 Broekaert WF, Marien W, Terras FR et al. Antimicrobial peptides from Amaranthus caudatus seeds with sequence homology to the cysteine/glycine-rich domain of chitin-binding proteins. Biochemistry (Mosc.) 31(17), 4308–4314 (1992).
    • 63 Rogozhin EA, Slezina MP, Slavokhotova AA et al. A novel antifungal peptide from leaves of the weed Stellaria media L. Biochimie 116, 125–132 (2015).
    • 64 Zhu S. Discovery of six families of fungal defensin-like peptides provides insights into origin and evolution of the CSalphabeta defensins. Mol. Immunol. 45(3), 828–838 (2008).
    • 65 Palicz Z, Jenes Á, Gáll T et al. In vivo application of a small molecular weight antifungal protein of Penicillium chrysogenum (PAF). Toxicol. Appl. Pharmacol. 269(1), 8–16 (2013).
    • 66 Belguesmia Y, Choiset Y, Rabesona H et al. Antifungal properties of durancins isolated from Enterococcus durans A5–11 and of its synthetic fragments. Lett. Appl. Microbiol. 56(4), 237–244 (2013).
    • 67 Kim YG, Kang HK, Kwon K-D, Seo CH, Lee HB, Park Y. Antagonistic activities of novel peptides from Bacillus amyloliquefaciens PT14 against Fusarium solani and Fusarium oxysporum. J. Agric. Food Chem. 63(48), 10380–10387 (2015).
    • 68 Seibold M, Wolschann P, Bodevin S, Olsen O. Properties of the bubble protein, a defensin and an abundant component of a fungal exudate. Peptides 32(10), 1989–1995 (2011).
    • 69 Ouedraogo JP, Hagen S, Spielvogel A, Engelhardt S, Meyer V. Survival strategies of yeast and filamentous fungi against the antifungal protein AFP. J. Biol. Chem. 286(16), 13859–13868 (2011).
    • 70 Tu C-Y, Chen Y-P, Yu M-C, Hwang I-E, Wu D-Y, Liaw L-L. Characterization and expression of the antifungal protein from Monascus pilosus and its distribution among various Monascus species. J. Biosci. Bioeng. 122(1), 27–33 (2016).
    • 71 Lin Z, Falkinham JO, Tawfik KA et al. Burkholdines from Burkholderia ambifaria: antifungal agents and possible virulence factors. J. Nat. Prod. 75(9), 1518–1523 (2012).
    • 72 Ongena M, Jacques P. Bacillus lipopeptides: versatile weapons for plant disease biocontrol. Trends Microbiol. 16(3), 115–125 (2008).
    • 73 Qi G, Zhu F, Du P et al. Lipopeptide induces apoptosis in fungal cells by a mitochondria-dependent pathway. Peptides 31(11), 1978–1986 (2010).
    • 74 Bui TH, Wray V, Nimtz M et al. Balticidins A–D, antifungal hassallidin-like lipopeptides from the Baltic Sea cyanobacterium Anabaena cylindrica Bio33. J. Nat. Prod. 77(6), 1287–1296 (2014).
    • 75 Chomcheon P, Wiyakrutta S, Aree T et al. Curvularides A–E: antifungal hybrid peptide-polyketides from the endophytic fungus Curvularia geniculata. Chem. Eur. J. 16(36), 11178–11185 (2010).
    • 76 Singh SB, Ondeyka J, Harris G et al. Isolation, structure, and biological activity of Phaeofungin, a cyclic lipodepsipeptide from a Phaeosphaeria sp. using the genome-wide Candida albicans fitness test. J. Nat. Prod. 76(3), 334–345 (2013).
    • 77 Samir P, Link AJ. Analyzing the cryptome: uncovering secret sequences. AAPS J. 13(2), 152–158 (2011). • Concise but comprehensive review on different approaches and proteomic tools for discovering, identifying and characterizing cryptides.
    • 78 Li R-F, Yan X-H, Lu Y-B et al. Anti-candidal activity of a novel peptide derived from human chromogranin A and its mechanism of action against Candida krusei. Exp. Ther. Med. 10(5), 1768–1776 (2015).
    • 79 De Zoysa M, Nikapitiya C, Whang I, Lee JS, Lee J. Abhisin: a potential antimicrobial peptide derived from histone H2A of disk abalone (Haliotis discus discus). Fish Shellfish Immunol. 27(5), 639–646 (2009).
    • 80 Shamova OV, Orlov DS, Balandin SV et al. Acipensins – novel antimicrobial peptides from leukocytes of the russian sturgeon Acipenser gueldenstaedtii. Acta Naturae 6(4), 99–109 (2014).
    • 81 Harris M, Mora-Montes HM, Gow NAR, Coote PJ. Loss of mannosylphosphate from Candida albicans cell wall proteins results in enhanced resistance to the inhibitory effect of a cationic antimicrobial peptide via reduced peptide binding to the cell surface. Microbiology 155(4), 1058–1070 (2009).
    • 82 Petit VW, Rolland J-L, Blond A et al. A hemocyanin-derived antimicrobial peptide from the penaeid shrimp adopts an alpha-helical structure that specifically permeabilizes fungal membranes. BBA Gen. Subjects 1860(3), 557–568 (2016).
    • 83 Liepke C, Baxmann S, Heine C, Breithaupt N, Ständker L, Forssmann W-G. Human hemoglobin-derived peptides exhibit antimicrobial activity: a class of host defense peptides. J. Chromatogr. B 791(1–2), 345–356 (2003).
    • 84 Yin C, Wong JH, Ng TB. Recent studies on the antimicrobial peptides lactoferricin and lactoferrampin. Curr. Mol. Med. 14(9), 1139–1154 (2014).
    • 85 Lis M, Liu TT, Barker KS, Rogers PD, Bobek LA. Antimicrobial peptide MUC7 12-mer activates the calcium/calcineurin pathway in Candida albicans. FEMS Yeast Res. 10(5), 579–586 (2010).
    • 86 Bobek LA, Situ H. MUC7 20-Mer: investigation of antimicrobial activity, secondary structure, and possible mechanism of antifungal action. Antimicrob. Agents Chemother. 47(2), 643–652 (2003).
    • 87 Koo YS, Kim JM, Park IY et al. Structure–activity relations of parasin I, a histone H2A-derived antimicrobial peptide. Peptides 29(7), 1102–1108 (2008).
    • 88 Wang C-W, Yip B-S, Cheng H-T et al. Increased potency of a novel d-β-naphthylalanine-substituted antimicrobial peptide against fluconazole-resistant fungal pathogens. FEMS Yeast Res. 9(6), 967–970 (2009).
    • 89 Di Giampaolo A, Luzi C, Casciaro B, Bozzi A, Luisa Mangoni M, Aschi M. P-113 peptide: new experimental evidences on its biological activity and conformational insights from molecular dynamics simulations. Biopolymers (Peptide Sci.) 102(2), 159–167 (2014).
    • 90 Machado A, Sforca ML, Miranda A et al. Truncation of amidated fragment 33–61 of bovine alpha-hemoglobin: effects on the structure and anticandidal activity. Biopolymers 88(3), 413–426 (2007).
    • 91 Wagener J, Schneider JJ, Baxmann S et al. A peptide derived from the highly conserved protein GAPDH is involved in tissue protection by different antifungal strategies and epithelial immunomodulation. J. Invest. Dermatol. 133(1), 144–153 (2013).
    • 92 Polonelli L, Magliani W, Conti S et al. Therapeutic activity of an engineered synthetic killer antiidiotypic antibody fragment against experimental mucosal and systemic candidiasis. Infect. Immun. 71(11), 6205–6212 (2003).
    • 93 Polonelli L, Ciociola T, Magliani W et al. Peptides of the constant region of antibodies display fungicidal activity. PLoS ONE 7(3), e34105 (2012).
    • 94 Klotz SA, Gaur NK, Rauceo J et al. Inhibition of adherence and killing of Candida albicans with a 23-Mer peptide (Fn/23) with dual antifungal properties. Antimicrob. Agents Chemother. 48(11), 4337–4341 (2004).
    • 95 Kabir ME, Karim N, Krishnaswamy S et al. Peptide derived from anti-idiotypic single-chain antibody is a potent antifungal agent compared with its parent fungicide HM-1 killer toxin peptide. Appl. Microbiol. Biotechnol. 92(6), 1151–1160 (2011).
    • 96 Polonelli L, Ponton J, Elguezabal N et al. Antibody complementarity-determining regions (CDRs) can display differential antimicrobial, antiviral and antitumor activities. PLoS ONE 3(6), e2371 (2008).
    • 97 Catania A, Cutuli M, Garofalo L et al. The neuropeptide α-MSH in host defense. Ann. NY Acad. Sci. 917(1), 227–231 (2000).
    • 98 da Costa J, Cova M, Ferreira R, Vitorino R. Antimicrobial peptides: an alternative for innovative medicines? Appl. Microbiol. Biotechnol. 99(5), 2023–2040 (2015). • Recent mini-review on available strategies for AMPs synthesis and bioinformatic tools for rational design of novel therapeutic agents.
    • 99 Midura-Nowaczek K, Markowska A. Antimicrobial peptides and their analogs: searching for new potential therapeutics. Perspect. Medicin. Chem. 6, 73–80 (2014).
    • 100 Schibli DJ, Epand RF, Vogel HJ, Epand RM. Tryptophan-rich antimicrobial peptides: comparative properties and membrane interactions. Biochem. Cell Biol. 80(5), 667–677 (2002).
    • 101 Maurya IK, Thota CK, Sharma J et al. Mechanism of action of novel synthetic dodecapeptides against Candida albicans. Biochim. Biophys. Acta 1830(11), 5193–5203 (2013).
    • 102 Chu H-L, Yu H-Y, Yip B-S et al. Boosting salt resistance of short antimicrobial peptides. Antimicrob. Agents Chemother. 57(8), 4050–4052 (2013).
    • 103 Rossignol T, Kelly B, Dobson C, d'Enfert C. Endocytosis-mediated vacuolar accumulation of the human ApoE apolipoprotein-derived ApoEdpL-W antimicrobial peptide contributes to its antifungal activity in Candida albicans. Antimicrob. Agents Chemother. 55(10), 4670–4681 (2011).
    • 104 Kamysz E, Sikorska E, Karafova A, Dawgul M. Synthesis, biological activity and conformational analysis of head-to-tail cyclic analogues of LL37 and histatin 5. J. Pept. Sci. 18(9), 560–566 (2012).
    • 105 Arnusch CJ, Ulm H, Josten M et al. Ultrashort peptide bioconjugates are exclusively antifungal agents and synergize with cyclodextrin and amphotericin B. Antimicrob. Agents Chemother. 56(1), 1–9 (2012).
    • 106 Makovitzki A, Avrahami D, Shai Y. Ultrashort antibacterial and antifungal lipopeptides. Proc. Natl Acad. Sci. USA 103(43), 15997–16002 (2006).
    • 107 Carmona-Ribeiro AM, de Melo Carrasco LD. Novel formulations for antimicrobial peptides. Int. J. Mol. Sci. 15(10), 18040–18083 (2014). • Review describing new formulations for improvement of AMPs therapeutic index.
    • 108 Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13(9), 655–672 (2014).
    • 109 Viana JF, Carrijo J, Freitas CG et al. Antifungal nanofibers made by controlled release of sea animal derived peptide. Nanoscale 7(14), 6238–6246 (2015).
    • 110 Kong EF, Tsui C, Boyce H et al. Development and in vivo evaluation of a novel Histatin-5 bioadhesive hydrogel formulation against oral candidiasis. Antimicrob. Agents Chemother. 60(2), 881–889 (2016).
    • 111 Saladino R, Botta G, Crucianelli M. Advances in the synthesis of bioactive unnatural amino acids and peptides. Mini Rev. Med. Chem. 12(4), 277–300 (2012).
    • 112 Comegna D, Benincasa M, Gennaro R, Izzo I, De Riccardis F. Design, synthesis and antimicrobial properties of non-hemolytic cationic α-cyclopeptoids. Biorg. Med. Chem. 18(5), 2010–2018 (2010).
    • 113 Larsen CE, Larsen CJ, Franzyk H, Regenberg B. Antifungal properties of peptidomimetics with an arginine-[beta-(2,5,7-tri-tert-butylindol-3-yl)alanine]-arginine motif against Saccharomyces cerevisiae and Zygosaccharomyces bailii. FEMS Yeast Res. 15(3), pii: fov011 (2015).
    • 114 Raman N, Lee MR, Lynn DM, Palecek SP. Antifungal activity of 14-helical beta-peptides against planktonic cells and biofilms of Candida species. Pharmaceuticals 8(3), 483–503 (2015).
    • 115 Seo MD, Won HS, Kim JH, Mishig-Ochir T, Lee BJ. Antimicrobial peptides for therapeutic applications: a review. Molecules 17(10), 12276–12286 (2012).
    • 116 Sharma H, Mathew B, Nagaraj R. Engineering of a linear inactive analog of human beta-defensin 4 to generate peptides with potent antimicrobial activity. J. Pept. Sci. 21(6), 501–511 (2015).
    • 117 Ghosh C, Haldar J. Membrane-active small molecules: designs inspired by antimicrobial peptides. Chem. Med Chem. 10(10), 1606–1624 (2015).
    • 118 López-Abarrategui C, McBeth C, Mandal SM et al. Cm-p5: an antifungal hydrophilic peptide derived from the coastal mollusk Cenchritis muricatus (Gastropoda: Littorinidae). FASEB J. 29(8), 3315–3325 (2015).
    • 119 Choi H, Hwang JS, Kim H, Lee DG. Antifungal effect of CopA3 monomer peptide via membrane-active mechanism and stability to proteolysis of enantiomeric D-CopA3. Biochem. Biophys. Res. Commun. 440(1), 94–98 (2013).
    • 120 Lee J, Lee D, Choi H et al. Synthesis and antimicrobial activity of cysteine-free coprisin nonapeptides. Biochem. Biophys. Res. Commun. 443(2), 483–488 (2014).
    • 121 Shin SH, Lee YS, Shin YP et al. Therapeutic efficacy of halocidin-derived peptide HG1 in a mouse model of Candida albicans oral infection. J. Antimicrob. Chemother. 68(5), 1152–1160 (2013).
    • 122 Carvalho LA, Remuzgo C, Perez KR, Machini MT. Hb40–61a: novel analogues help expanding the knowledge on chemistry, properties and candidacidal action of this bovine alpha-hemoglobin-derived peptide. Biochim. Biophys. Acta 1848(12), 3140–3149 (2015).
    • 123 Magliani W, Conti S, Ciociola T et al. Killer peptide: a novel paradigm of antimicrobial, antiviral and immunomodulatory auto-delivering drugs. Future Med. Chem. 3(9), 1209–1231 (2011).
    • 124 Fázio MA, Jouvensal L, Vovelle F et al. Biological and structural characterization of new linear gomesin analogues with improved therapeutic indices. Biopolymers (Peptide Sci.) 88(3), 386–400 (2007).
    • 125 Falla TJ, Hancock RE. Improved activity of a synthetic indolicidin analog. Antimicrob. Agents Chemother. 41(4), 771–775 (1997).
    • 126 Puig M, Moragrega C, Ruz L et al. Interaction of antifungal peptide BP15 with Stemphylium vesicarium, the causal agent of brown spot of pear. Fungal Biol. 120(1), 61–71 (2016).
    • 127 Thankappan B, Jeyarajan S, Hiroaki S, Anbarasu K, Natarajaseenivasan K, Fujii N. Antimicrobial and antibiofilm activity of designed and synthesized antimicrobial peptide, KABT-AMP. Appl. Biochem. Biotechnol. 170(5), 1184–1193 (2013).
    • 128 Theberge S, Semlali A, Alamri A, Leung K, Rouabhia M. C. albicans growth, transition, biofilm formation, and gene expression modulation by antimicrobial decapeptide KSL-W. BMC Microbiol. 13(1), 246 (2013).
    • 129 Lum KY, Tay ST, Le CF et al. Activity of novel synthetic peptides against Candida albicans. Sci. Rep. 5, 9657 (2015).
    • 130 Wu J-M, Wei S-Y, Chen H-L, Weng K-Y, Cheng H-T, Cheng J-W. Solution structure of a novel D-naphthylalanine substituted peptide with potential antibacterial and antifungal activities. Biopolymers (Peptide Sci.) 88(5), 738–745 (2007).
    • 131 Wu H, Ong ZY, Liu S et al. Synthetic β-sheet forming peptide amphiphiles for treatment of fungal keratitis. Biomaterials 43, 44–49 (2015).
    • 132 Cao H, Ke T, Liu R et al. Identification of a novel proline-rich antimicrobial peptide from Brassica napus. PLoS ONE 10(9), e0137414 (2015).
    • 133 Zielińska P, Staniszewska M, Bondaryk M, Koronkiewicz M, Urbańczyk-Lipkowska Z. Design and studies of multiple mechanism of anti-Candida activity of a new potent Trp-rich peptide dendrimers. Eur. J. Med. Chem. 105, 106–119 (2015).
    • 134 Muñoz A, Marcos JF, Read ND. Concentration-dependent mechanisms of cell penetration and killing by the de novo designed antifungal hexapeptide PAF26. Mol. Microbiol. 85(1), 89–106 (2012).
    • 135 Lopez-Garcia B, Harries E, Carmona L et al. Concatemerization increases the inhibitory activity of short, cell-penetrating, cationic and tryptophan-rich antifungal peptides. Appl. Microbiol. Biotechnol. 99(19), 8011–8021 (2015).
    • 136 Kaspar AA, Reichert JM. Future directions for peptide therapeutics development. Drug Discov. Today 18(17–18), 807–817 (2013).
    • 137 Uhlig T, Kyprianou T, Martinelli FG et al. The emergence of peptides in the pharmaceutical business: from exploration to exploitation. EuPA Open Proteomics 4, 58–69 (2014).
    • 138 Adis Insight. http://adisinsight.springer.com/.
    • 139 Kang S-J, Park SJ, Mishig-Ochir T, Lee B-J. Antimicrobial peptides: therapeutic potentials. Expert Rev. Anti Infect. Ther. 12(12), 1477–1486 (2014).
    • 140 De Lucca AJ. Antifungal peptides: potential candidates for the treatment of fungal infections. Expert Opin. Investig. Drugs 9(2), 273–299 (2000).
    • 141 Blondelle SE, Lohner K. Combinatorial libraries: a tool to design antimicrobial and antifungal peptide analogues having lytic specificities for structure–activity relationship studies. Biopolymers 55(1), 74–87 (2000).
    • 142 Hammami R, Fliss I. Current trends in antimicrobial agent research: chemo- and bioinformatics approaches. Drug Discov. Today 15(13–14), 540–546 (2010).
    • 143 Danishuddin M, Khan AU. Structure based virtual screening to discover putative drug candidates: necessary considerations and successful case studies. Methods 71, 135–145 (2015).
    • 144 Di Luca M, Maccari G, Nifosi R. Treatment of microbial biofilms in the post-antibiotic era: prophylactic and therapeutic use of antimicrobial peptides and their design by bioinformatics tools. Pathog. Dis. 70(3), 257–270 (2014).
    • 145 Medina Marrero R, Marrero-Ponce Y, Barigye SJ et al. QuBiLs-MAS method in early drug discovery and rational drug identification of antifungal agents. SAR QSAR Environ. Res. 26(11), 943–958 (2015).
    • 146 Scotti L, Tullius Scotti M, de Oliveira Lima E et al. Experimental methodologies and evaluations of computer-aided drug design methodologies applied to a series of 2-aminothiophene derivatives with antifungal activities. Molecules 17(3), 2298–2315 (2012).
    • 147 Beckloff N, Laube D, Castro T et al. Activity of an antimicrobial peptide mimetic against planktonic and biofilm cultures of oral pathogens. Antimicrob. Agents Chemother. 51(11), 4125–4132 (2007).
    • 148 Diehnelt CW. Peptide array based discovery of synthetic antimicrobial peptides. Front. Microbiol. 4, 402 (2013).
    • 149 Maurya IK, Thota CK, Verma SD et al. Rationally designed transmembrane peptide mimics of the multidrug transporter protein Cdr1 act as antagonists to selectively block drug efflux and chemosensitize azole-resistant clinical isolates of Candida albicans. J. Biol. Chem. 288(23), 16775–16787 (2013).
    • 150 Lempers VJ, Brüggemann RJ. Antifungal therapy: drug–drug interactions at your fingertips. J. Antimicrob. Chemother. 71(2), 285–289 (2015).
    • 151 Mora-Navarro C, Caraballo-Leon J, Torres-Lugo M, Ortiz-Bermudez P. Synthetic antimicrobial beta-peptide in dual-treatment with fluconazole or ketoconazole enhances the in vitro inhibition of planktonic and biofilm Candida albicans. J. Pept. Sci. 21(12), 853–861 (2015).
    • 152 Tati S, Li R, Puri S, Kumar R, Davidow P, Edgerton M. Histatin 5-spermidine conjugates have enhanced fungicidal activity and efficacy as a topical therapeutic for oral candidiasis. Antimicrob. Agents Chemother. 58(2), 756–766 (2014).
    • 153 Ferreira SZ, Carneiro HC, Lara HA et al. Synthesis of a new peptid–coumarin conjugate: a potential agent against cryptococcosis. ACS Med. Chem. Lett. 6(3), 271–275 (2015).
    • 154 Lim K, Chua RR, Bow H, Tambyah PA, Hadinoto K, Leong SS. Development of a catheter functionalized by a polydopamine peptide coating with antimicrobial and antibiofilm properties. Acta Biomater. 15, 127–138 (2015).
    • 155 Raman N, Marchillo K, Lee MR et al. Intraluminal release of an antifungal beta-peptide enhances the antifungal and anti-biofilm activities of multilayer-coated catheters in a rat model of venous catheter infection. ACS Biomater. Sci. Eng. 2(1), 112–121 (2016).
    • 156 Bugli F, Caprettini V, Cacaci M et al. Synthesis and characterization of different immunogenic viral nanoconstructs from rotavirus VP6 inner capsid protein. Int. J. Nanomedicine 9, 2727–2739 (2014).
    • 157 McCloskey AP, Gilmore BF, Laverty G. Evolution of antimicrobial peptides to self-assembled peptides for biomaterial applications. Pathogens 3(4), 791–821 (2014).
    • 158 Wang H, Xu K, Liu L et al. The efficacy of self-assembled cationic antimicrobial peptide nanoparticles against Cryptococcus neoformans for the treatment of meningitis. Biomaterials 31(10), 2874–2881 (2010).
    • 159 Kovalainen M, Monkare J, Riikonen J et al. Novel delivery systems for improving the clinical use of peptides. Pharmacol. Rev. 67(3), 541–561 (2015). • Good review on novel controlled peptide delivery systems.