Enhancing proline-rich antimicrobial peptide action by homodimerization: influence of bifunctional linker

Li, Wenyi; Lin, Feng; Hung, Andrew; Barlow, Anders J.; Sani, Marc‐Antoine; Paolini, Rita; Singleton, William; Holden, Joseph; Hossain, Mohammed Akhter; Separovic, Frances; O'Brien-Simpson, Neil M; Wade, John D.

doi:10.1039/d1sc05662j

Cited by 34 publications

(36 citation statements)

References 52 publications

(63 reference statements)

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“…It also enabled us to compare the results obtained here with the ones previously obtained with the pre-formulation procedure, in which the thiol-terminated peptides were grafted on the polymer chain through Michael addition [12]. Indeed, when dealing with peptides, choice of the linker is not trivial and without consequences, since even the slightest modification can alter the peptide's behavior [24,25]. It has been notably recently highlighted with radiolabeled peptide derivatives, for which the chelate conjugated to the peptide demonstrated a significant influence [26,27].…”

Section: Discussionmentioning

confidence: 70%

Hepatotropic Peptides Grafted onto Maleimide-Decorated Nanoparticles: Preparation, Characterization and In Vitro Uptake by Human HepaRG Hepatoma Cells

et al. 2022

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We recently demonstrated the strong tropism of George Baker (GB) Virus A (GBVA10-9) and Plasmodium circumsporozoite protein (CPB) derived synthetic peptides towards hepatoma cells. In a first approach, these peptides were covalently bound to poly(benzyl malate) (PMLABe73) and poly(ethylene glycol)-block-PMLABe73 (PEG62-b-PMLABe73) (co)polymers, and corresponding peptide-decorated nanoparticles (NPs) were prepared by nanoprecipitation. We showed that peptide enhanced NPs internalization by hepatoma cells. In the present work, we set up a second strategy to functionalize NPs prepared from PMLABe73 derivates. First, maleimide-functionalized PMLABe73 (Mal-PMLABe73) and PEG62-b-PMLABe73 (Mal-PEG62-b-PMLABe73) were synthesized and corresponding NPs were prepared by nanoprecipitation. Then, peptides (GBVA10-9, CPB and their scramble controls GBVA10-9scr and CPBscr) with a thiol group were engrafted onto the NPs’ maleimide groups using the Michael addition to obtain peptide functionalized NPs by post-formulation procedure. These peptide-modified NPs varied in diameter and dispersity depending on the considered peptides and/or (co)polymers but kept their spherical shape. The peptide-functionalized NPs were more efficiently internalized by HepaRG hepatoma cells than native and maleimide-NPs with various levels relying on the peptide’s nature and the presence of PEG. We also observed important differences in internalization of NPs functionalized by the maleimide-thiol-peptide reaction compared to that of NPs prepared from peptide-functionalized PMLABe73 derivatives.

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Section: Discussionmentioning

confidence: 70%

Hepatotropic Peptides Grafted onto Maleimide-Decorated Nanoparticles: Preparation, Characterization and In Vitro Uptake by Human HepaRG Hepatoma Cells

et al. 2022

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“…This dual mode of action of PP30, membrane lysis and DnaK activation, is novel and unreported for other native PrAMPs. Interestingly a dimeric form of the artificial PrAMP Chex-Arg20, A3-APO ( Szabo et al, 2010 ), has been shown to be predominantly membrane-lytic ( Li et al, 2017 ; 2022 ). The dual mode of action of PP30 has not however resulted in observable MICs in the assays here which may be due to a range of factors.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Potential DnaK Modulating Proline-Rich Antimicrobial Peptides Identified by Computational Screening

Handley

Welch

et al. 2022

Front. Chem.

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The day is rapidly approaching where current antibiotic therapies will no longer be effective due to the development of multi-drug resistant bacteria. Antimicrobial peptides (AMPs) are a promising class of therapeutic agents which have the potential to help address this burgeoning problem. Proline-rich AMPs (PrAMPs) are a sub-class of AMPs, that have multiple modes of action including modulation of the bacterial protein folding chaperone, DnaK. They are highly effective against Gram-negative bacteria and have low toxicity to mammalian cells. Previously we used an in silico approach to identify new potential PrAMPs from the DRAMP database. Four of these peptides, antibacterial napin, attacin-C, P9, and PP30, were each chemically assembled and characterized. Together with synthetic oncocin as a reference, each peptide was then assessed for antibacterial activity against Gram-negative/Gram-positive bacteria and for in vitro DnaK modulation activity. We observed that these peptides directly modulate DnaK activity independently of eliciting or otherwise an antibiotic effect. Based on our findings, we propose a change to our previously established PrAMP definition to remove the requirement for antimicrobial activity in isolation, leaving the following classifiers: >25% proline, modulation of DnaK AND/OR the 70S ribosome, net charge of +1 or more, produced in response to bacterial infection AND/OR with pronounced antimicrobial activity.

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“…Class I PrAMPs, such as Bac7, Onc112, pyrrhocoricin, and metalnikowin, interfere with the initial step of translation to block the peptide transferase center and the peptide exit channel of the ribosome [128], whereas class II PrAMPs, such as apidaecin 1b and Api137, act during translation termination and inhibit protein synthesis by trapping release factors on the 70S ribosome following hydrolysis of the nascent polypeptide chain [129]. There are quite a few recent studies on PrAMPs, which attempt to enhance the antibacterial activity of PrAMPs against bacteria, even drug-resistant bacteria, through de novo synthesis, chemical modification and other methods [130][131][132]. A recent study showed that the PrAMP dimers produced by the bifunctional linker significantly enhanced their antibacterial and anti-biofilm activities against a variety of Gram-negative bacilli, including drug-resistant Acinetobacter baumannii strains [132].…”

Section: Amps Acting On Intracellular Targetsmentioning

confidence: 99%

Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides

Zuo

Wang

et al. 2022

Molecules

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Antimicrobial peptides are a type of small-molecule peptide that widely exist in nature and are components of the innate immunity of almost all living things. They play an important role in resisting foreign invading microorganisms. Antimicrobial peptides have a wide range of antibacterial activities against bacteria, fungi, viruses and other microorganisms. They are active against traditional antibiotic-resistant strains and do not easily induce the development of drug resistance. Therefore, they have become a hot spot of medical research and are expected to become a new substitute for fighting microbial infection and represent a new method for treating drug-resistant bacteria. This review briefly introduces the source and structural characteristics of antimicrobial peptides and describes those that have been used against common clinical microorganisms (bacteria, fungi, viruses, and especially coronaviruses), focusing on their antimicrobial mechanism of action and clinical application prospects.

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Enhancing proline-rich antimicrobial peptide action by homodimerization: influence of bifunctional linker

Abstract: Homodimerization of a proline-rich antimicrobial peptide via bioconjugation to perfluoroaromatic linkers confers increased antimicrobial, antibiofilm and immunomodulatory activity. The dimers are promising new therapeutic leads against WHO priority multidrug resistant bacteria.

Cited by 34 publications

References 52 publications

Hepatotropic Peptides Grafted onto Maleimide-Decorated Nanoparticles: Preparation, Characterization and In Vitro Uptake by Human HepaRG Hepatoma Cells

Hepatotropic Peptides Grafted onto Maleimide-Decorated Nanoparticles: Preparation, Characterization and In Vitro Uptake by Human HepaRG Hepatoma Cells

Evaluation of Potential DnaK Modulating Proline-Rich Antimicrobial Peptides Identified by Computational Screening

Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides

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