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Antimicrobial PeptidesAntimicrobial Peptides
An ancient immune system?An ancient immune system?
oror
This frog could save This frog could save youryour leg leg
Huh?
Antimicrobial peptides:Antimicrobial peptides:Where are they?Where are they?
In everything from Amoebas to HumansIn everything from Amoebas to Humans Abundant in vertebrates in: Abundant in vertebrates in: • External MucosaExternal Mucosa– eyes, mouth, genitourinary, skin, lung, tracheaeyes, mouth, genitourinary, skin, lung, trachea
• Immune cellsImmune cells– neutrophilsneutrophils
• Intestinal tract (duodenum)Intestinal tract (duodenum)– in humans; Paneth cells are the sourcein humans; Paneth cells are the source
Cationic, AmphipathicCationic, Amphipathic• Linear Linear -helical (20-35 AA)-helical (20-35 AA)
–Magainin, cecropins, histatinMagainin, cecropins, histatin
• Pro-Arg rich (more polar)Pro-Arg rich (more polar)– bac 5 and 7 (30-50 AA; 70% pro/arg)bac 5 and 7 (30-50 AA; 70% pro/arg)
• Disulfide Rich Disulfide Rich -structure-structure– amoebapores, NK-lysinamoebapores, NK-lysin
• Disulfide Rich Disulfide Rich -structure-structure– Defensins: three or more disulfide (30-70 AA)Defensins: three or more disulfide (30-70 AA)– “ “Loops” (11-22 AA)Loops” (11-22 AA)
• tachpyylesins, protegrins ,ranalexin, polymyxintachpyylesins, protegrins ,ranalexin, polymyxin
Antimicrobial peptides:Antimicrobial peptides:What are they?What are they?
HUMAN HUMAN PLANT PLANT
Defensin-likeDefensin-like
Helical: PGLa(frog)Helical: PGLa(frog)
Small ProteinsSmall Proteins• lysozymelysozyme• phospholipase aphospholipase a• cathepsinscathepsins
Antimicrobial peptides:Antimicrobial peptides:What are they?What are they?
AntifungalAntifungal AntibacterialAntibacterial• Gram positiveGram positive
• Gram negativeGram negative
Antimicrobial peptides:Antimicrobial peptides:What do they do?What do they do?
cell wall cell wall
cell wall cell wall
OMOM
LPSLPS
membranemembrane
membranemembrane
Permeabilize OM, IMPermeabilize OM, IM• channelschannels• lysislysis
– D-analogs sometimes as effectiveD-analogs sometimes as effective
Carry LPSCarry LPS• immune stimulation?immune stimulation?
Enzyme actionEnzyme action• cell wall destructioncell wall destruction• lipase , proteaselipase , protease
– synergistic w/cationic peptides?synergistic w/cationic peptides?
Antimicrobial peptides:Antimicrobial peptides:What do they do?What do they do?
Bacteria have :Bacteria have :• more negative chargemore negative charge– recall: peptides are cationicrecall: peptides are cationic
• no sterols, little phosphatidylcholine or SMno sterols, little phosphatidylcholine or SM• a lot of PG/PE/cardiolipin/PSa lot of PG/PE/cardiolipin/PS– some tumor cells too!some tumor cells too!
Antimicrobial peptides:Antimicrobial peptides:Why are they picky?Why are they picky?
NFNFB-type genetic element seems B-type genetic element seems universaluniversal• like acute phase response in humanslike acute phase response in humans
Protective anionic piece is common,Protective anionic piece is common,
Antimicrobial peptides:Antimicrobial peptides:How are they made?How are they made?
signalsignal propiecepropiece maturemature
Mechanisms?Mechanisms?
Indolicidin analog fights test infectionsIndolicidin analog fights test infections• IP or IVIP or IV
Protegrin analog Protegrin analog • helps chemotherapy oral mucositishelps chemotherapy oral mucositis
Magainin analog, LOCILEX™ Cream underwent Magainin analog, LOCILEX™ Cream underwent clinical trials (now Genaera Corporation )clinical trials (now Genaera Corporation )• diabetic ulcers, not approveddiabetic ulcers, not approved• Squalamine, amino sterol cationic peptide analog-Squalamine, amino sterol cationic peptide analog-
anti-obesity and anti angiogenesisanti-obesity and anti angiogenesis
Antimicrobial peptides:Antimicrobial peptides:New Clinical Antibiotics?New Clinical Antibiotics?
Proteolysis, Salt, Transport propertiesProteolysis, Salt, Transport properties ManufactureManufacture
– chemical synthesis is very chemical synthesis is very expensive;$100’s/gram!expensive;$100’s/gram!
– organic mimics or modular design may helporganic mimics or modular design may help–May be possible to produce in bacteria or May be possible to produce in bacteria or
plantsplants• protective piece for bacteriaprotective piece for bacteria• TMV with tobacco (GENEWARETMV with tobacco (GENEWARE®®))
Antimicrobial peptides:Antimicrobial peptides:Problems with use?Problems with use?