All‐D‐magainin: chirality, antimicrobial activity and proteolytic resistance

doi:10.1016/0014-5793(90)81351-n

Cited by 273 publications

(62 citation statements)

References 28 publications

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“…The issue of net charge has been observed previously by our group for cephalothin-Bac8c conjugates, where activity was incompletely masked (50). The use of D-amino acids, which have been shown to be resistant to proteolysis (51)(52)(53), may be necessary to avoid deactivation by the abundant proteases of the CF lung. In addition, any potential candidate would have to be compatible with local lung delivery such as is used with tobramycin and colistin in treatment of CF (3,6,54).…”

Section: Figmentioning

confidence: 78%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of Pseudomonas aeruginosa to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of P. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 g/ml). Cytotoxic effects on CFBE41o-cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at in vivo concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

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Section: Figmentioning

confidence: 78%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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“…Because the L and D forms of peptides are known to have different stability to proteases [14, 33, 34], we also followed the digestion of TetraF2W-RK by a set of important proteases from both host and pathogens. This includes mammalian chymotrypsin, trypsin, S. aureus V8 protease, and fungal proteinase K. Interestingly, the L-form of TetraF2W-RK was not cut by trypsin and the S. aureus V8 protease at a peptide:protease molar ratio of 40:1, although it was completely degraded by chymotrypsin and fungal proteinase K in 24 h. In the case of the D-form, TetraF2W-RK remained stable to all the proteases tested here (Fig.…”

Section: Resultsmentioning

confidence: 99%

Design and surface immobilization of short anti-biofilm peptides

et al. 2017

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Short antimicrobial peptides are essential to keep us healthy and their lasting potency can inspire the design of new types of antibiotics. This study reports the design of a family of eight-residue tryptophan-rich peptides (TetraF2W) obtained by converting the four phenylalanines in temporin-SHf to tryptophans. The temporin-SHf template was identified from the antimicrobial peptide database (http://aps.unmc.edu/AP). Remarkably, the double arginine variant (TetraF2W-RR) was more effective in killing methicillin-resistant Staphylococcus aureus (MRSA) USA300, but less cytotoxic to human skin HaCat and kidney HEK293 cells, than the lysine-containing dibasic combinations (KR, RK and KK). Killing kinetics and fluorescence spectroscopy suggest membrane targeting of TetraF2W-RR, making it more difficult for bacteria to develop resistance. Because established biofilms on medical devices are difficult to remove, we chose to covalently immobilize TetraF2W-RR onto the polyethylene terephthalate (PET) surface to prevent biofilm formation. The successful surface coating of the peptide is supported by FT-IR and XPS spectroscopies, chemical quantification, and antibacterial assays. This peptide-coated surface indeed prevented S. aureus biofilm formation with no cytotoxicity to human cells. In conclusion, TetraF2W-RR is a short Trp-rich peptide with demonstrated antimicrobial and anti-biofilm potency against MRSA in both the free and immobilized forms. Because these short peptides can be synthesized cost effectively, they may be developed into new antimicrobial agents or used as surface coating compounds.

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“…Ninhydrin assay was utilized to monitor the coupling efficacy. For synthesis of (KLAKLAK) 2 sequence, D-amino acids were used for avoiding proteolysis62. (4-Carboxybutyl) triphenylphosphonium bromide and Rhodamine B was coupled using the similar method to amino acid.…”

Section: Methodsmentioning

confidence: 99%

Multifunctional Enveloped Mesoporous Silica Nanoparticles for Subcellular Co-delivery of Drug and Therapeutic Peptide

Luo

Chen

Liu

et al. 2014

Sci Rep

155

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A multifunctional enveloped nanodevice based on mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Mesoporous silica MCM-41 nanoparticles were used as the core for loading antineoplastic drug topotecan (TPT). The surface of nanoparticles was decorated with mitochondria-targeted therapeutic agent (Tpep) containing triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK) 2 via disulfide linkage, followed by coating with a charge reversal polyanion poly(ethylene glycol)-blocked-2,3-dimethylmaleic anhydride-modified poly(L-lysine) (PEG-PLL(DMA)) via electrostatic interaction. It was found that the outer shielding layer could be removed at acidic tumor microenvironment due to the degradation of DMA blocks and the cellular uptake was significantly enhanced by the formation of cationic nanoparticles. After endocytosis, due to the cleavage of disulfide bonds in the presence of intracellular glutathione (GSH), pharmacological agents (Tpep and TPT) could be released from the nanoparticles and subsequently induce specific damage of tumor cell mitochondria and nucleus respectively with remarkable synergistic antitumor effect.D uring the last decades, intense efforts have been made to construct various drug nanocarriers based on metals 1 , metal oxides 2-4 , micelles 5 , and liposomes 6 for tumor-targeted drug delivery. However, there are many physiological barriers for the nanocarrier reaching the particular target site, including circulating from the blood compartments to the tumor extracellular matrix, sticking to tumor-cell membrane for fast cell internalization, releasing the encapsulated cargo within cells, and targeting to subcellular sites of action in turn. Recently, enveloped nanodevice of programmatically packing the nano-core with different functional groups has been proposed to surmount all these physiological barriers 7,8 . For example, PEGylation is widely used as a stealthy layer for avoiding quick recognition of the carriers by the immune system and thereby extending blood circulation time 9,10 . Moreover, for resisting protein adsorption, negatively charged carriers can be used to block the interaction with cell membrane due to electrostatic repulsion 11 . Nevertheless, positively charged nanoparticles can enter cells easily because of their high affinity to negatively charged cell membrane, although they display rapid clearance from blood circulation 12 . Thus, it is highly desirable to fabricate PEGlated and charge switchable nanoparticles that exhibit good shielding effect against normal cells with a prolonged circulation time, but alter their surface charge at tumor site and become sticky targeting to tumor cells. Positive nanoparticles were reported with the capability to strip stealth layer at acidic environment and re-expose the positively charged surface for improving tumor cell uptake by employing a tumor acidity-sensitive PEGlated anionic polymer 13 .For internalization of nanoparticles by tumor cells, it is e...

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All‐D‐magainin: chirality, antimicrobial activity and proteolytic resistance

Cited by 273 publications

References 28 publications

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Design and surface immobilization of short anti-biofilm peptides

Multifunctional Enveloped Mesoporous Silica Nanoparticles for Subcellular Co-delivery of Drug and Therapeutic Peptide

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