Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds PDF
Preview Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds
Journal of Fungi Review Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds MałgorzataBondaryk1,MonikaStaniszewska1,* ID,PaulinaZielin´ska2and ZofiaUrban´czyk-Lipkowska2,* 1 NationalInstituteofPublicHealth-NationalInstituteofHygiene,Chocimska24,00-791Warsaw,Poland; [email protected] 2 InstituteofOrganicChemistry,PolishAcademyofSciences,01-224Warsaw,Poland; [email protected] * Correspondence:[email protected](M.S.);zofi[email protected](Z.U.-L.); Tel.:+48-22-542-12-28(M.S.);+48-343-22-07(Z.U.-L.) Received:27July2017;Accepted:22August2017;Published:26August2017 Abstract: Invasivefungalinfectionsareassociatedwithhighmortalityrates,despiteappropriate antifungaltherapy. Limitedtherapeuticoptions,resistancedevelopmentandthehighmortalityof invasivefungalinfectionsbroughtaboutmoreconcerntriggeringthesearchfornewcompounds capableofinterferingwithfungalviabilityandvirulence. Inthiscontext,peptidesgainedattention as promising candidates for the antimycotics development. Variety of structural and functional characteristicsidentifiedforvariousnaturalantifungalpeptidesmakesthemexcellentstartingpoints fordesignnoveldrugcandidates. Currentreviewprovidesabriefoverviewofnaturalandsynthetic antifungalpeptides. Keywords: antifungalpeptides;fungalpathogens;Candidaspecies 1. Introduction The increased prevalence of fungal infections is a consequence of the advances in medicinal technologies and therapies applied in critically ill patients [1]. Expanding immunocompromised population due to multi-organ failure or critical illness along with other clinical factors (Table 1) can increase the incidence of invasive fungal infections (IFI) [2–6]. IFI are of great concern due to highmorbidityandmortalityrates[7]. Over90%ofIFI-relateddeathsresultfrominfectionsdueto Candidaspp.,Aspergillusspp.,Cryptococcusspp. andPneumocystisspp.[7,8]. Table1.Riskfactorsforthedevelopmentofinvasivefungalinfections(IFI). RiskFactors References Abdominalsurgery/recentmajorsurgery [3,5,9,10] Deepburns [11,12] Diabetesmellitus [9,10,12] Dialysis [12,13] Disturbanceofnaturalskinormucosalbarriers [10,12] Exposuretobroad-spectrumantibiotics [3,10,12] Extremesofage [5,10] HIV/AIDS [9,13] Immunedisorders [5,11] Localdisordersofthegastrointestinaltract [5,10,12] Long-termcatheterization [3,5,13] Malignancies [3,5] J.Fungi2017,3,46;doi:10.3390/jof3030046 www.mdpi.com/journal/jof J.Fungi2017,3,46 2of36 Table1.Cont. RiskFactors References Mechanicalventilation [10,13] Parenteralnutrition [5,10,13] Prematureverylowbirthweightinfants [11] Prolongedhospitalization [12] Renalfailure [9,11,12] Solidorganorbonemarrowtransplantation [5] Treatmentwithcorticosteroids [3,5] Useofimmunosuppressivedrugs [5,10,12] Currently available antifungal agents, based on their mode of action, can be divided to five classes: polyenes, azoles, echinocandins, pyrimidine analogs and allylamines [14–19]. Of these, allylamines are used against superficial infections, while the four remaining drug categories are effectiveagainstinvasivemycoses[19]. Onlytwoclassesofsystemicantifungalagentsareconsidered to be non-toxic: triazoles (fluconazole and voriconazole) and echinocandins (caspofungin and micafungin)[14]. Therefore,currentguidelinesofEuropeanSocietyforClinicalMicrobiologyand InfectiousDiseases(ESCMID)stronglyrecommendtheuseoffluconazoleempiricaltherapyagainst invasive candidiasis in patients who recently underwent abdominal surgery and had recurrent gastrointestinalperforations[20]. Moreover,ESCMIDstronglyrecommendstheuseofechinocandins forthetargetedinitialtreatmentofcandidaemia[20,21]. Widespread use of antifungal agents in therapy and prolonged treatment often leads to the resistancedevelopment[19]. Resistancemechanismsweredescribedforallcommerciallyavailable antifungal agents (Table 2). Rising antifungal resistance is a major problem especially in case of fluconazole, a drug of choice for candidiasis treatment in AIDS patients [22]. Recent surveillance studies from various medical centers worldwide have documented the rise in echinocandins’ resistance; especially among C. glabrata isolates [14,19,23]. The need for novel, safe and effective antifungal agents increases in parallel with the expanding number of resistant fungal isolates [23,24]. Recent reports[25,26] have demonstrated the success of the combination of antifungal therapy regimens that utilize new generation antifungals (third generation azoles and lipopeptides—echinocandins)againstseveremycoses.Ontheotherhand,caspofunginandpresumably otherechinocandinshavenotbeenfoundtobeaneffectivetreatmentforendemicmycoses,suchas Histoplasmacapsulatum[27,28],remainingoneofthemostfearedcomplicationsofimmunosuppression duetoitssignificantmorbidityandmortality[29,30]. Inthisregard,amphotericinB(AmB)remains highly active invitro against the fungi responsible for Histoplasma infections [31–33]. Itraconazole istheprimaryazoleformostendemicmycoseswithitsserumdruglevelmaintainedatthesteady stateof≥0.5mg/mL,whichisparticularlyimportantinpatientswithsevereinfections[31,32,34,35]. Alternativelytoitaconazole’slimitations(lackoftolerance,absorptionproblemsorgastrointestinal intolerability) other azoles (fluconazole, voriconazole or posaconazole) are recommended [31,32]. Asregardsthis,whilethethird-generationazoleshaveexcellentinvitroandinvivoactivityagainst Histoplasma [36,37], H. capsulatum develops resistance to fluconazole during therapy, leading to relapse[38,39]. Thus,H.capsulatum’santigenconcentrationsinserumandurineshouldbemonitored everythreetosixmonthstoprovideevidencethatthemaintenancetherapycontinuestosuppressthe progressionofinfection[38,39]. Standard antifungal therapies such as the azole family and AmB are not effective against Pneumocystispneumonia(PCP),duetoP.jiroveci(previouslyP.cariniif. sp. hominis),possiblydueto thelackofergosterolbiosynthesisbythesefungi[40]. WhilesomereportssuggestefficacyagainstPCP withtheuseofanidulafungin,caspofungin,ormicafunginaloneorincombinationwithastandard anti-PCPagent: trimethoprim-sulfamethoxazoleoratovaquoneonealone[41,42],othersdidnotreport sucheffects[43–46]. Asmuchasanidulafunginandcaspofunginaremoreeffectivethanmicafungin J.Fungi2017,3,46 3of36 inreducingcystcounts, theyhaveotherrestrictionsasdescribedbelow. FindingsofCushionand Collins[47]suggestthatthebiofilmformationinthemammalianlungisapotentialmechanismby whichthesefungimightresistthetherapeuticinterventions.Abrogationofechinocandins’activitywith theadditionofhumanserumhasbeenreportedforP.jiroveciaswellasC.glabrata[48]. Cushionand Collins[47]showedthatP.jiroveciismoresusceptibletotheechinocandinsinthesuspensionassay thaninthebiofilmsystems. Novel antifungal agent should have a broad-spectrum activity, target specificity, low toxicity, diverse mode of action, and no antagonistic effects with commercially available drugs [49,50]. Althoughsuchdrugmaybeunattainableinreality,thesepropertiesshouldbeusedasguidelinesin drugdiscovery[51]. Recently,thereisanincreasedinterestintopeptidesasapromisingapproach indiscoveryanddevelopmentofnovelantifungalagents. Thisreviewprovidesabriefoverviewof naturalandsyntheticantifungalpeptides. J.Fungi2017,3,46 4of36 Table2.Fivemajorgroupsofantifungalagents. GroupName GroupMember/s ModeofAction ResistanceMechanism References • Deficiencyinenzymesinvolvedinpyrimidinesalvage FluorinatedPyrimidine Flucytosine(5-FC) InhibitionofRNAand/orDNAsynthesis and5-FCmetabolism [15,52] Analogs • MutationsinFCA1,FUR1,FCY21,FCY22 • DefectsintheERG3gene(loweredergosterolcontent incellmembrane) Nystatin Alterationofthemembranefunctionbybindingof • Alteredmembranecomposition–substituted Polyenes Natamycin [18,52] ergosterol(depletingcellsofergosterol) nonergosterolcytoplasmicmembranesterolsand AmphotericinB lipids(e.g.,zymosterol,squalene) • CapsuleenlargementofC.neoformans Caspofungin Alterationofcellwallbiosynthesisbyinhibitionof • MutationintheFKS1andFKS2genes Echinocandins Micafungin [16,19] β(1,3)-glucansynthaseFks1porFks2p • Lackof1,3-β-glucaninthecellwallofC.neoformans Anidulafungin • Modificationofdrugtarget(missensemutationor Inhibitionoftheergosterolbiosynthesisby Terbinafine substitutionintheERG1) Allylamines inhibitionofsqualeneepoxidase(Erg1)and/or [16,19] Naftifine • Degradationofthenaphthaleneringcontained accumulationoftoxicsterolintermediates interbinafine • MutationsoroverexpressionofERG11 Fluconazole InhibitionofcytochromeP45014α-lanosterol • Reducedaccumulationoftheazolesinsidefungalcell Azoles Posoconazole demethylase(encodedbyERG11)inergosterol [16,19,52] (reduceduptakeofazoles,effluxviaABCtransporters) Voriconazole biosynthesispathway • TolerancetomethylatedsterolsviamutationinERG3 J.Fungi2017,3,46 5of36 2. AntifungalPeptides Development of novel antifungal compounds may overcome the problem of growing fungal resistance. Inthiscontext,peptideshavepromisingproperties,suchasmoderateimmunogenicity as described below, strong antimicrobial activity, high specificity and affinity for targets, distinct mechanisms of action, good organ and tissue penetration and broad-spectrum activity [49,50]. Antifungalpeptideshavediverseactionmechanisms, whichinclude: (1)inhibitionofDNA,RNA andproteinsynthesis;(2)bindingtoDNAorRNA;(3)membranepermeabilization;(4)inhibitionof thecellwallsynthesisandenzymeactivity;(5)inductionofapoptosis;and(6)repressionofprotein foldingandmetabolicturnover[49,53–55]. Antifungalpeptidescanbeclassifiedaccordingtotheir modeofactionandorigin[56]. Basedontheiractionmechanism,antifungalpeptidescanbedivided into: (1)membranetraversingpeptidesthatcancauseporeformationoractonspecifictargetsuch asβ-glucanorchitinsynthesis;and(2)nonmembranetraversingpeptidesthatinteractwiththecell membraneandcausecelllysis[56]. Accordingtotheirorigin,peptidescanbeclassifiedasnatural compoundsandsyntheticmoleculesisolatedfromgeneticorrecombinantlibrariesordiscoveredfrom chemicallibraries[56,57]. 2.1. NaturalPeptides In higher organisms, antimicrobial peptides are part of the first line of defense against pathogens, while in microorganisms they are used in competition for nutrient resources [58,59]. Naturalantimicrobialpeptidesusuallyshownoorlittletoxicityagainsthumancellsandarestablein variousconditions[60]. Theygenerallypossesscommonfeatures,suchassmallsize,overallpositive charge,cationicandamphipathicnature[50,59]. Antimicrobialpeptidescanbearrangedintodifferent groups based on their length, sequence and structure [50]. The first group is formed by α-helical peptides,whichmostlyexhibitarandomstructurebeforeinteractingwiththecellmembrane,and well-definedstructureafterwards[61]. Anotherlargegroupconsistsofpeptidesthatcontaincysteine residues,formdisulfidebondsandstableβ-structures(sheet,hairpin,andbarrel)[50,61]. Manyother antimicrobialpeptides(i.e.,defensins)havemixedstructureconsistingofacysteine-stabilizedαβ-motif (CSαβ)withα-helixandatriple-strandedantiparallelβ-sheetstabilizedbyfourdisulfidebonds[62]. The number of identified antimicrobial peptides exceeds 2700 and increases. Of these, over 900peptidesisolatedfrommicrobes,plantsandanimalsdisplayantifungalactivity[50,63]. Natural antifungalpeptidescanbederivatedfromdifferentsources,suchasbacteria,archea,protists,fungi, plantsandanimals(Table3). AsreviewedbyBasaketal.[64],antimicrobialpeptidesdisplayvariouslevelsoftoxicityagainst mammaliancells. Interestingly,theabilityofpeptidestoreactspecificallywiththefunctionalbinding siteofacomplementaryantibodyknownasantigenicityhasbeenwidelydescribed[65]. Thecytotoxic activity is related to the structural features of the peptide consisting of a cationic N-terminal sequencepredictedtoassumeanamphipathicα-helicalconformation(residues1–18)andaC-terminal hydrophobictail(residues19–27). Thehydrophobictailisresponsibleforthepeptideactivity,since itsanalog,BMAP28(1–18),whichcomprisesthe18N-terminalresidues,showedareductioninthe neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effect. Furthermore, BMAP28’s cytotoxicity requires an active metabolism of the target cells [66]. The cathelicidin-like peptide (SMAP-29)derivedfrommyeloidsheepwasstronglyhemolyticagainsthumanerythrocytes[26,67]. Human cathelicidin (LL-37) was found to regulate the inflammatory response and chemo-attract the cells of the adaptive immune system into wound or infection sites, helping to neutralize the microorganismandpromotingre-epithelizationandwoundclosure[68,69]. Rondoninderivedfrom thespiderAcanthoscurriarondoniaewiththeantifungalactivityshowednodeleteriousactivitiesagainst humanerythrocytesorGram-positiveandGram-negativebacteria. Temporinsidentifiedintheskin secretion of the European red frog Rana temporaria [70], did not lyse human erythrocytes [71–75]. Bovinecathelicidins(BMAP-28)withthefungicidalactivitywastoxicforthemammaliantumorcells, J.Fungi2017,3,46 6of36 inducingtheirapoptosis,anditalsoinducedmitochondrialpermeability,formingtransitionpores (MPTP),resultinginthereleaseofcytochromec. Conventional antimicrobial agents (penicillin and beta-lactams), which are small organic molecules,areusuallynotimmunogenic,althoughtheextendedlongertreatmentperiodsinimmune compromised or critically ill patients can trigger an immune response [76]. Peptide (NZ2114), a40-residuelongvariantofplectasin,inducedimmuneresponses[8]. Contrariwise,smallerpeptide, a pediocin AcH (class IIa bacteriocin) isolated form of Pediococcus acidilactici, displayed weak immunogenicity[14,15]. Cyclopeptidecolistin(1155Da)activeagainstmultiresistantAcinetobacter baumanniiandadministereddespiteitsneuro-andnephrotoxiceffectsdidnotshowimmunogenic effects[17]. Moreover,insectderivedproline-richintermediate-size(i.e.,15–25residues)antimicrobial linear peptides (PrAMPs) were usually weak immunogens. It was shown that they have to be cross-linked,oligomerizedorcoupledtolargercarrierproteinsorpolymerstotriggerastrongimmune response[18,19]. Antimicrobial peptides (i.e., cathelicidins and β-defensins) either directly defend the pathogens[77]orstimulateinflammatoryresponses[78,79],leadingtopro-inflammatorycytokine signaling[80]andtoll-likereceptor(TLR)activation[81].Thiscouldendupinactivatingandrecruiting immunecellstothesiteofinfectionandthusboostingthehostimmunedefense. Manyoriginally isolatedantifungalpeptidespossessimmunosuppressiveactivityblockingtherecipient’simmune system,thuspreventingatransplantedorganrejection[82,83]. Theyarealsoemployedtoslowdown theimmuneresponseinpatientssufferingfromcertainimmunedisorders[84]. JJ.. FFuunnggii 22001177,, 33,, 4466 77 ooff 3355 TTaabbllee 33.. NNaattuurraall ppeeppttiiddeess aaccttiivvee aaggaaiinnsstt ffuunnggii 11.. J.Fungi2017,3,4NN6aammee OOrriiggiinn SSeeqquueennccee oorr MMoolleeccuullaarr FFoorrmmuullaa MMooddee ooff AAccttiioonn RReeffeerreennccee 7of36 BBaacctteerriiaall PPeeppttiiddeess MMSSLLQQAANNTTAAPPVVFFAATDDaEEbQQleQQ3TT.DDNAAaPPtuTTrWWalPPpDDeRRpAAtiAdAeDDsPPaSScVVtiRRvLLeSSaLLgLLaAAinTTsGGtNfNuSSnLLgPPiVV1.VVIIEEPPTTAADDGGLLDDPPVVQQ SSyyrriinnggoommyycciinn WWAASSAARRRREEAAIIEETTLLLLCCRRHHGGAAVVLLFFRRGGFFDDLLPPSSVVAAAAFFEEGGFFAAEEAALLSSPPGGLLHHGGTTYYGGDDLLPPKKKKEEGGGGRRNN Name Origin SequenceorMolecularFormula ModeofAction Reference PPsseeuuddoommoonnaass VVYYRRSSTTPPYYPPEERREEMMIILLYYHHNNEESSSSHHLLEESSWWPPRRKKQQWWFFFFCCEEQQPPSSRRVVGGGGAATTPPLLAADDIIRRQQVVLLAAYYLLPPKKEEVV BacterialPeptides ssyyrriinnggaaee ppvv.. VVMEESRRLFFQEEASSKKNGGTLALLLPYYVSSFRRATTDFFETTQAAQGGTVVDEEAPPSSPWWTWEESSPFFDFFRGGATTSASEEDRRPSSSVVVIIREEQLQSRRLCCLRRAEETQQGGGNTTSDDLFPFEEVWWVILLEDDPGGTADDDTTLGLQQLDLLRRPTTVQQQCC CCeellll llyyssiiss [[8855––8899]] SSyyrrPP pprrootteeiinn ssyyrriinnggaaee PPWAAAVVSIIATTHRHRPPEFFTATGGIEEETRRLCCLFFCFFRNNHQQGVVAQQVLLLHHFHRHGPPYFYDCCLMMPGGSVEEAEELLARRFEEEDDGLLFLALDDEMAMLFFSGGPPPGDDLRRHLLGPPTRRYLLGVVSDSYYLGGPDKDGKGESSAGAIGIEERDDNPP VYRSTPYPEREMILYHNESSHLESWPRKQWFFCEQPSRVGGATPLADIRQVLAYLPKEV Syringomycin Pseudomonassyringae VVVMMERAAFLLEIISGGKEEGAALYYLEEYAASCRCTAAFVVTRRAFFGEEVWWERRPKKSWGGDDESVVFVVFMMGTLLSDDENNRMMSVLLIAAEAQAHRHCAARRREDDQPPGYYTEEDEEPFPRERWLLIIVLVDVVGAADMMTGGLEEQMMLTRTATAQRRGCG Celllysis [84–88] pv.syringae DDPAVVVWWITQQHPPPAAF TGERCFFNQVQLHHPYCMGEELREDLLDMFGPDRLPRLVSYGDGSAIEDP VMALIGEAYEACAVRFEWRKGDVVMLDNMLAAHARDPYEEPRLIVVAMGEMTARG SyrPprotein KKDIIVYYWGGVVQYYPMMADDRRPPLLSSAAGGEEEEVVRRMMMMAAAAVVSSAAEEKKRREEKKCCRRRRFFYYHHKKEEDDAAHHRRTTLLIIGGDDMMLLIIRRTTAAAAAAKKAA IIttuurriinn AA BBaacciilllluuss ssuubbttiilliiss YYKGGIYLLGDDVPPYAAMGGIDISSRFFGPGLVVSQQAEEGYYEGGEKKVPPRYYMIIPPMAAALLAPPDVDSMMAHHEFFKNNRIIESSKHHCSSRGGRRRFWWYIHIVVKCCEAADVVADDHSSRKKTPPLIIGGIGIIDDDIIMEEKKLMIMRKTKAPPGAGTATIIKDDAII CCeellll llyyssiiss [[8877,,8899,,9900]] IturinA Bacillussubtilis AAYKGKRRLFDFFFPSSAPPGTTIEESYYFSSGDDVLLQQQEAAYKKGHHKPPPDDYIQQPQAQTLTDPDDYYMFFYYHHHFLLNWWISSSHMMSKKGEERSSWFFIIIKKVQQCAAAVGGDKKSGGKLLPSSILLGPPILLDDDIESSKFFSSMVVKRRPLLGKKTDDIDDDGIG Celllysis [86,88,89] AKRFFSPTEYSDLQAKHPDQQTDYFYHLWSMKESFIKQAGKGLSLPLDSFSVRLKDDG HHHVVVSSSIIIEEELLL SSttrreeppttoommyycceess IInnhhiiIbbniithtiiioobnnit ooioff n cchhoiifttiinn NikkomNNyciikiknkkoommyycciinn Streptomycesspp. chitin [[9911––9933]] [90–92] sspppp.. bbiioossbyyinnottshhyeensstiihss esis Inhibitionof SSttrreeppttoommyycceess IInnhhiibbiittiioonn ooff PepstatiPnPeeAppssttaattiinn AA Streptomycesspp. aspartic [[9933]] [92] sspppp.. aassppaaprrrttoiicct epparrsooettseeaasseess FFuunnggaall PPeeppttiiddeess J.Fungi2017,3,46 8of36 Table3.Cont. Name Origin SequenceorMolecularFormula ModeofAction Reference J. Fungi 2017, 3, 46 8 of 35 FungalPeptides Inhibition of Aspergillus Inhibitionof AculeaciAncAuleacin A Aspergillusaculeatus 1,3-β1,-3D--βg-ldu-cgalnu can [93,94] [92,93] aculeatus synthase synthase PlantPeptides Plant Peptides Defensins Rs-AFP1Defensins QKLCERPSGTWSGVCGNNNACKNQCINLEKARHGSCNYVFPAHKCICYFPC Membrane Raphanussativus [62,88,94–96] Rs-AFP2Rs-AFP1 Raphanus QQKKLLCCEQRRPPSSGGTTWWSSGGVVCCGGNNNNNNAACCKKNNQQCCIINRLLEEKKAAWRHGGSCSCNNYYVVFFPAPAHHKKCCICICYYFPFCPC Mempebrrmaneea bilization [62,89,95–97] ThioninRss-AFP2 sativus QKLCQRPSGTWSGVCGNNNACKNQCIRLEKAWGSCNYVFPAHKCICYFPC permeabilization KEICCKVPTTPFLCTNDPQCKTLCSKVNYEDGHCFDILSKCVCMNRCVQDAKTLAAEL Membrane CaThi Thionins Capsicumannuum IEEEFLKQ permeabilization [88,97,98] Thaumatin-like(TL)proteiCnaspsicum KEICCKVPTTPFLCTNDPQCKTLCSKVNYEDGHCFDILSKCVCMNRCVQDAKTLAAEL Membrane CaThi [89,98,99] annuum IAETEIEEFVLRKNQN CPYTVWAASTPIGGGRRLDRGQTWVINAPRGTKMARVWGRTNCNFNAA permCeeallbwiliazlaltion GRGTCQTGDCGGVLQCTGWGKPPNTLAEYALDQFSGLDFWDISLVDGFNIPMTFAPT Osmotin Nicotianatabacum perturbations; Thaumatin-like (TL) proteins NPSGGKCHAIHCTANINGECPRELRVPGGCNNPCTTFGGQQYCCTQGPCGPTFFSKFF sporelysis KQRCPDAYSYPQDDPTSTFTCPGGSTNYRVIFCPNGQAHPNFPLEMPGSDEVAK [86,88,99,100] ATIEVRNNCPYTVWAASTPIGGGRRLDRGQTWVINAPRGTKMARVWGRTNCNFNAA AAVFTVVNQCPFTVWAASVPVGGGRQLNRGESWRITAPAGTTAARIWARTGCKFDA Cell wall Nicotiana GSGRRGGTCSCQRTTGGDDCCGGGGVVLLQQCCTTGGWYGGKRAPPPNNTTLLAAEEYYAALLDKQQFFNSGNLLDDFFWFDDIISSLLIVDDGGFFNNVIPPMMSTFFLAPPDT Zeamatin Zeamays Celllysis Osmotin GGSGCSRGPRCAVDVNARCPAELRQDGVCNNACPVFKKDEYCCVGSAANDCHPTN perturbations; tabacum NPSGGKCHAIHCTANINGECPRELRVPGGCNNPCTTFGGQQYCCTQGPCGPTFFSKFF YSRYFKGQCPDAYSYPKDDATSTFTCPAGTNYKVVFCP spore lysis KQRCPDAYSYPQDDPTSTFTCPGGSTNYRVIFCPNGQAHPNFPLEMPGSDEVAK [87,89,100,101] AAVFTVVNQCPFTVWAASVPVGGGRQLNRGESWRITAPAGTTAARIWARTGCKFDA SGRGSCRTGDCGGVLQCTGYGRAPNTLAEYALKQFNNLDFFDISLIDGFNVPMSFLPD Zeamatin Zea mays Cell lysis GGSGCSRGPRCAVDVNARCPAELRQDGVCNNACPVFKKDEYCCVGSAANDCHPTN YSRYFKGQCPDAYSYPKDDATSTFTCPAGTNYKVVFCP Insect Peptides J.Fungi2017,3,46 9of36 Table3.Cont. Name Origin SequenceorMolecularFormula ModeofAction Reference InsectPeptides Cecropins Stomoxyn Stomoxyscalcitrans RGFRKHFNKLVKKVKHTISETAHVAKDTAVIAGSGAAVVAAT Celllysis [54,88,101] Proapoptotic Melittin Apismellifera GIGAVLKVLTTGLPALISWIKRKRQQ-CONH2 activity [102,103] Defensins Drosophila Drosomycin DCLSGRYKGPCAVWDNETCRRVCKEEGRSSGHCSPSLKCWCEGC Celllysis [86,88,104] melanogaster DHHDGHLGGHQTGHQGGQQGGHLGGQQGGHLGGHQGGQPGGHLGGHQGGIGG Tenecin3 Tenebriomolitor Unknown TGGQQHGQHGPGTGAGHQGGYKTHGH YGPGDGHGGGHGGGHGGGHGNGQGGGHGHGPGGGFGGGHGGGHGGGGRGGGG [71,88,105] Holotricin3 Holotrichiadiomphalia SGGGGSPGHGAGGGYPGGHGGGHHGGYQTHGY Growth Pseudacanthotermes inhibition Termicin ACNFQSCWATCQAQHSIYFRRAFCDRSQCKCVFVRG spiniger AmphibianPeptides Disrubtionof Magainin2 Xenopuslaevis GIGKFLHSAKKFGKAFVGEIMNS plasma [106–108] membrane BuforinI Bufobufogaragriozans AGRGKQGGKVRAKAKTRSSRAGLQFPVGRVHRLLRKGNY Celllysis [55,106] BuforinII TRSSRAGLQFPVGRVHRLLRK TemporinA Ranatemporaria FLPLIGRVLSGIL Celllysis [56,88,109] Phyllomedusa Membrane Dermaseptin-1 GLWSTIKNVGKEAAIAAGKAALGAL [86,88,110,111] hypochondrialis permeabilization J.Fungi2017,3,46 10of36 Table3.Cont. Name Origin SequenceorMolecularFormula ModeofAction Reference AvianPeptides Avianβ-defensins Gallinacins GRKSDCFRKSGFCAFLKCPSLTLISGKCSRFYLCCKRIWG Gallusgallus β-defensin-4 IVLLFVAVHGAVGFSRSPRYHMQCGYRGNFCTPGKCPHGNAYPGLCRPKYSCCRW THP-1 Meleagrisgallopavo GKREKCLRRNGFCAFLKCPTLSVISGTCSRFQVCC Celllysis [86,88,112–115] Aptenodytes Spheniscin-1 SFGLCRLRRGFCAHGRCRFPSIPIGRCSRFVQCCRRVW patagonicus Cathelicidins Cathelicidin-2 Gallusgallus LVQRGRFGRFLRKIRRFRPKVTITIQGSARFG Celllysis [88,116] MammalianPeptides α-defensins HNP-1 ACYCRIPACIAGERRYGTCIYQGRLWAFCC Homosapiens HNP-2 CYCRIPACIAGERRYGTCIYQGRLWAFCC Celllysis [86,88,117,118] MSSRHSPYPRKTSGDTTGSKTSWASSGSRENKGNHKNPSFSTASRPFLTRQQKKEILKPR ALRKDPPKVFCATHRADSPDAPAVCGFFWHSNRIAGKGTDWIFTRGKQLFQERAKNN NP-1 Rabbitbocaparvovirus VIDWDMARDLLFSFKRECDQWYRNMLYHFRLGEPCDKCNYWDGAYRKYCARVNAD YEKEINATSASQELTDEEAAAALDAAMADASH β-defensins HBD-1 DHYNCVSSGGQCLYSACPIFTKIQGTCYRGKAKCCK HBD-2 Homosapiens TCLKSGAICHPVFCPRRYKQIGTCGLPGTKCCKKP Celllysis [88,118–120] HBD-3 GIINTLQKYYCRVRGGRCAVLSCLPKEEQIGKCSTRGRKCCRRKK HBD-4 ELDRICGYGTARCRKKCRSQEYRIGRCPNTYACCLRK
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