Roles of d-Amino Acids on the Bioactivity of Host Defense Peptides

Li, Hao; Anuwongcharoen, Nuttapat; Malik, Aijaz Ahmad; Prachayasittikul, Virapong; Wikberg, Jarl E. S.; Nantasenamat, Chanin

doi:10.3390/ijms17071023

Cited by 58 publications

(56 citation statements)

References 145 publications

(246 reference statements)

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“…The observation made in this study is consistent with previous experimental results of Oren and Shai (1997), which stipulates that hydrophobicity and charge are the primary determinants of antimicrobial activities of AMPs. The same observation was made by a number of research and review articles (Čeřovský et al, 2008;Li et al, 2016;Toro Segovia et al, 2017) where all of which made the observation that positive charge and amphipahicity was important for AMP antimicrobial activity. In fact, positive charge is a key recognition feature of AMPs and antimicrobial activity could be significantly increased by simply adding more positively charged amino acids to the peptides (Papo and Y, 2003).…”

Section: Global Descriptor Detailssupporting

confidence: 53%

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Peer Review #2 of "Toward insights on determining factors for high activity in antimicrobial peptides via machine learning (v0.2)"

2019

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The continued and general rise of antibiotic resistance in pathogenic microbes is a wellrecognized global threat. Host defense peptides (HDPs), a component of the innate immune system have demonstrated promising potential to become a next generation antibiotic effective against a plethora of pathogens. While the effectiveness of antimicrobial host defense peptides (AMPs) has been extensively demonstrated in experimental studies, theoretical insights on the mechanism by which these peptides function is comparably limited. In particular, experimental studies of AMP mechanisms are limited in the number of different peptides investigated and the type of peptide parameters considered. This study makes use of the random forest algorithm for classifying the antimicrobial activity as well for identifying molecular descriptors underpinning the antimicrobial activity of investigated peptides. Subsequent manual interpretation of the identified important descriptors revealed that polarity-solubility are necessary for the membrane lytic antimicrobial activity of HDPs.

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Section: Global Descriptor Detailssupporting

confidence: 53%

“…In previous articles (Li et al, 2016;Shoombuatong et al, 2018), we had investigated the field of HDP extensively and can attest that there is a plethora of computational studies on HDPs investigating the classification of HDPs on the basis of their target pathogen class (e.g. bacteria, cancer, parasites, etc.)…”

Section: Introductionmentioning

confidence: 99%

Peer Review #2 of "Toward insights on determining factors for high activity in antimicrobial peptides via machine learning (v0.2)"

2019

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“…28). In this study we found that D-form KLKLLLLLKLK-NH 2 showed higher antimicrobial activity against both Gram-positive and Gram-negative bacteria, including S. aureus and E. coli , relative to its L-form counterpart.…”

Section: Discussionmentioning

confidence: 99%

D-form KLKLLLLLKLK-NH2 peptide exerts higher antimicrobial properties than its L-form counterpart via an association with bacterial cell wall components

Manabe

Kawasaki

2017

Sci Rep

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The antimicrobial peptide KLKLLLLLKLK-NH2 was developed based on sapesin B, and synthesized using D-amino acids. Biochemical properties of the D-form and L-form KLKLLLLLKLK-NH2 peptides were compared. In order to limit the effects due to bacterial resistance to proteolysis, antimicrobial activities of the peptides were evaluated after short-term exposure to bacteria. D-form KLKLLLLLKLK-NH2 exhibited higher antimicrobial activities than L-form KLKLLLLLKLK-NH2 against bacteria, including Staphylococcus aureus and Escherichia coli. In contrast, both the D-form and L-form of other antimicrobial peptides, including Mastoparan M and Temporin A, exhibited similar antimicrobial activities. Both the D-form KLKLLLLLKLK-NH2 and L-form KLKLLLLLKLK-NH2 peptides preferentially disrupted S. aureus-mimetic liposomes over mammalian-mimetic liposomes. Furthermore, the D-form KLKLLLLLKLK-NH2 increased the membrane permeability of S. aureus more than the L-form KLKLLLLLKLK-NH2. Thus suggesting that the enhanced antimicrobial activity of the D-form was likely due to its interaction with bacterial cell wall components. S. aureus peptidoglycan preferentially inhibited the antimicrobial activity of the D-form KLKLLLLLKLK-NH2 relative to the L-form. Furthermore, the D-form KLKLLLLLKLK-NH2 showed higher affinity for S. aureus peptidoglycan than the L-form. Taken together, these results indicate that the D-form KLKLLLLLKLK-NH2 peptide has higher antimicrobial activity than the L-form via a specific association with bacterial cell wall components, including peptidoglycan.

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“…Because AMPs typically do not exert their direct antibiotic activity by specific structural affinities, dynamic metabolic stability can be gained by assembling the prodrug sequence from heterochiral residues. Thus, the AMP itself is assembled from D‐amino acids, whereas the promoiety and linker are made of L‐amino acids . For example, fusion sequences encompassing an oligo‐glutamate, a neutrophil elastase (NE)‐sensitive tetrapeptide motif (AAAG), and an all‐D AMP could target Pseudomonas aeruginosa in chronically infected cystic fibrosis (CF) patients.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the AMP itself is assembled from D-amino acids, whereas the promoiety and linker are made of L-amino acids. 21 For example, fusion sequences encompassing an oligo-glutamate, a neutrophil elastase (NE)-sensitive tetrapeptide motif (AAAG), and an all-D AMP could target Pseudomonas aeruginosa in chronically infected cystic fibrosis (CF) patients. These prodrug candidates can confine the activity of linear AMPs to the endobronchial space and reduce the toxicity of their parent peptides in vivo.…”

mentioning

confidence: 99%

Action of antimicrobial peptides and their prodrugs on model and biological membranes

Forde

Shafiy

Fitzgerald-Hughes

et al. 2018

Journal of Peptide Science

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Antimicrobial peptides (AMPs) are promising broad-spectrum antibiotic candidates in the wake of multi-drug resistant pathogens. Their clinical use still requires a solution based on lead optimisation and/or formulation to overcome certain limitations, such as unwanted cytotoxicity. A prodrug approach could overcome this safety barrier and can be achieved through reversible reduction or neutralisation of the AMPs' net cationic charge. By prodrug activation through pathogen associated enzymes, this approach could increase the therapeutic index of membrane active peptides. P18, a cecropin/magainin hybrid, and WMR, a myxinidin analogue from hagfish, were used as templates for the design strategy. The membrane permeabilizing activities of these AMPs and their prodrugs are reported here for liposomes of either Escherichia coli polar lipid extract or a human model lipid system of phosphatidylcholine and cholesterol. These results are compared with their antibacterial and haemolytic activities. Overall, correlation between liposome permeabilization and the corresponding bioactivity is observed and indicate that the broad-spectrum antibacterial effect exerted by these peptides is associated with membrane disruption. Furthermore, the prodrug modification had a general negative influence on membrane disruption and bioactivity, notably as much on bacterial as on human membranes. This prodrug strategy is particularly successful when complete neutralisation of the AMP's net charge occurs. Thus, on-target selectivity between bacterial and human membranes can be improved, which may be used to prevent the unnecessary exposure of host cells and commensal bacteria to active AMPs.

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Roles of d-Amino Acids on the Bioactivity of Host Defense Peptides

Cited by 58 publications

References 145 publications

Peer Review #2 of "Toward insights on determining factors for high activity in antimicrobial peptides via machine learning (v0.2)"

Peer Review #2 of "Toward insights on determining factors for high activity in antimicrobial peptides via machine learning (v0.2)"

D-form KLKLLLLLKLK-NH2 peptide exerts higher antimicrobial properties than its L-form counterpart via an association with bacterial cell wall components

Action of antimicrobial peptides and their prodrugs on model and biological membranes

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