Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds

36 Pages·2017·1.32 MB·English

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.:[phone](M.S.);[phone](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]
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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
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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
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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,
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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
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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