A pH-dependent charge reversal peptide for cancer targeting

Wakabayashi, Naoko; Yano, Yoshiaki; Kawano, Kenichi

doi:10.1007/s00249-016-1145-y

Cited by 21 publications

(16 citation statements)

References 38 publications

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“…To address this issue, a peptide based on magainin 2 from X. laevis was designed to possess a negative charge at neutral pH that switched to a strong positive charge at low pH for cancer targeting. Designated HE, this novel peptide, killed human renal adenocarcinoma at low pH via membranolytic mechanisms and was nontoxic towards healthy human cells across low and neutral pH conditions, making it a promising lead compound for cancer therapy [313]. As a further example, chronic infections due to P. aeruginosa are responsible for the majority of the morbidity and mortality in patients with CF and the persistence of these infections is largely due to the organism adopting a biofilm mode of growth, thereby acquiring high resistance to most antibiotics [314,315].…”

Section: Discussionmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.

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Section: Discussionmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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“…In contrast to bacterial membranes, the outer monolayers of eukaryotic membranes are composed of zwitterionic (overall neutral) lipids, thereby partly explaining selectivity between eukaryotic and prokaryotic cells. Notably, cancer cells lose some of the membrane asymmetry between the inner and outer monolayer, thereby making their outside more negative, which may explain why some cationic peptides are also active against cancer cells (Wakabayashi et al 2016).…”

Section: Action On the Bacterial Cell Membranementioning

confidence: 99%

Antimicrobial Peptides: Mechanisms of Action and Resistance

2016

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More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide's structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

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“…In addition to differences in the surface charges of membranes, ART peptides are assumed to have another mechanism of cell selectivity. The pH values just above the lipid membranes decreased as the anionic components of the membranes increased . ART peptides become more cationic just above cancer cell membranes than that above normal cell membranes.…”

Section: Discussionmentioning

confidence: 97%

“…Metastatic or multidrug‐resistant cancer tissues are considered to have an even lower pH than that of other cancer tissues . In our previous research, the acidic environment in cancer tissues was used to improve the selectivity of F5W‐substituted magainin 2 (MG); a well‐studied anticancer peptide isolated from Xenopus laevis . A peptide with larger cationic charges at a weakly acidic pH than that at neutral pH should exhibit stronger electrostatic interactions with anionic membranes in cancer tissues.…”

Section: Introductionmentioning

confidence: 99%

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Endowment of pH Responsivity to Anticancer Peptides by Introducing 2,3‐Diaminopropionic Acid Residues

Tanishiki

Yano

2019

ChemBioChem

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Endowment of pH responsivity to anticancer peptides is a promising approach to achieve better selectivity to cancer tissues. In this research, a template peptide was designed based on magainin 2, an antimicrobial peptide with anticancer activity, and a series of peptides were designed by replacing different numbers of lysine with the unnatural amino acid, 2,3diaminopropionic acid (Dap), which has a positive charge at weakly acidic pH in cancer tissues, but is neutral at physiological pH 7.4. These Dap‐containing peptides are expected to interact more strongly with tumor cells than with normal cells because 1) weakly acidic conditions form in tumors, and 2) the membrane of tumor cells is more anionic than that of normal cells. Although all examined peptides showed potent cytotoxicities to multidrug‐resistant cancer cells at a weakly acidic pH (ED50≈5 μm), the toxicity decreased with an increase in the number of Dap at pH 7.4 (8 Dap residues resulted in ED50≈60 μm). Furthermore, the introduction of Dap reduced cytotoxicity against normal cells. Thus, Dap led to significantly improved cancer targeting due to a pH‐dependent charge shift. Fluorescence imaging and model membrane experiments supported this charge‐shift model.

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A pH-dependent charge reversal peptide for cancer targeting

Cited by 21 publications

References 38 publications

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

Antimicrobial Peptides: Mechanisms of Action and Resistance

Endowment of pH Responsivity to Anticancer Peptides by Introducing 2,3‐Diaminopropionic Acid Residues

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