Strategies to Stabilize Cell Penetrating Peptides for<i>In Vivo</i>Applications

Fominaya, Jesús; Bravo, Jerónimo; Rebollo, Angelita

doi:10.4155/tde.15.51

Cited by 45 publications

(50 citation statements)

References 197 publications

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“…Treatment with TP4 has also been previously reported to reduce bacterial ( Helicobacter pylori ) loads in mice [5]. There are several ways to stabilize TP3 or TP4 in vivo , such as using liposome-packaged peptides, nanoparticles, or D-form peptides [31,32], but these experimental methods are not suitable for aquacultural applications due to cost issues. Therefore, additional analyses are required to determine the best strategy for peptide stabilization and reducing the costs associated with the manufacture of TP3 or TP4 in fish fodder.…”

Section: Discussionmentioning

confidence: 99%

Study of the Antimicrobial Activity of Tilapia Piscidin 3 (TP3) and TP4 and Their Effects on Immune Functions in Hybrid Tilapia (Oreochromis spp.)

Pan

Tsai

et al. 2017

PLoS ONE

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To address the growing concern over antibiotic-resistant microbial infections in aquatic animals, we tested several promising alternative agents that have emerged as new drug candidates. Specifically, the tilapia piscidins are a group of peptides that possess antimicrobial, wound-healing, and antitumor functions. In this study, we focused on tilapia piscidin 3 (TP3) and TP4, which are peptides derived from Oreochromis niloticus, and investigated their inhibition of acute bacterial infections by infecting hybrid tilapia (Oreochromis spp.) with Vibrio vulnificus and evaluating the protective effects of pre-treating, co-treating, and post-treating fish with TP3 and TP4. In vivo experiments showed that co-treatment with V. vulnificus and TP3 (20 μg/fish) or TP4 (20 μg/fish) achieved 95.3% and 88.9% survival rates, respectively, after seven days. When we co-injected TP3 or TP4 and V. vulnificus into tilapia and then re-challenged the fish with V. vulnificus after 28 days, the tilapia exhibited survival rates of 35.6% and 42.2%, respectively. Pre-treatment with TP3 (30 μg/fish) or TP4 (20 μg/fish) for 30 minutes prior to V. vulnificus infection resulted in high survival rates of 28.9% and 37.8%, respectively, while post-treatment with TP3 (20 μg/fish or 30 μg/fish) or TP4 (20 μg/fish) 30 minutes after V. vulnificus infection yielded high survival rates of 33.3% and 48.9%. In summary, pre-treating, co-treating, and post-treating fish with TP3 or TP4 all effectively decreased the number of V. vulnificus bacteria and promoted significantly lower mortality rates in tilapia. The minimum inhibitory concentrations (MICs) of TP3 and TP4 that were effective for treating fish infected with V. vulnificus were 7.8 and 62.5 μg/ml, respectively, whereas the MICs of kanamycin and ampicillin were 31.2 and 3.91 μg/ml. The antimicrobial activity of these peptides was confirmed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM), both of which showed that V. vulnificus disrupted the outer membranes of cells, resulting in the loss of cell shape and integrity. We examined whether TP3 and TP4 increased the membrane permeability of V. vulnificus by measuring the fluorescence resulting from the uptake of 1-N-phenyl-naphthylamine (NPN). Treating fish with TP3 and TP4 under different pH and temperature conditions did not significantly increase MIC values, suggesting that temperature and the acid-base environment do not affect AMP function. In addition, the qPCR results showed that TP3 and TP4 influence the expression of immune-responsive genes, including interleukin (IL)-1β, IL-6, and IL-8. In this study, we demonstrate that TP3 and TP4 show potential for development as drugs to combat fish bacterial infections in aquaculture.

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Section: Discussionmentioning

confidence: 99%

Study of the Antimicrobial Activity of Tilapia Piscidin 3 (TP3) and TP4 and Their Effects on Immune Functions in Hybrid Tilapia (Oreochromis spp.)

Pan

Tsai

et al. 2017

PLoS ONE

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“…Despite the potential of CPPs as vectors for cargo delivery, their use is limited by their rapid degradation by endogenous proteases. To overcome this limitation, several strategies have been employed to improve the stability of CPPs, including the introduction of non‐proteinogenic amino acids or higher structural rigidity . Herein, we evaluated if the peptide sequence conversion into well‐structured Agl‐AA oligomer increased the proteolytic resistance of 2 c prior to its use for the delivery of bioactive molecules.…”

Section: Methodsmentioning

confidence: 99%

Ribbon‐like Foldamers for Cellular Uptake and Drug Delivery

et al. 2017

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Different intracellular delivery systems of bioactive compounds have been developed, including cell-penetrating peptides. Although usually nontoxic and biocompatible, these vectors share some of the general drawbacks of peptides, notably low bioavailability and susceptibility to protease degradation, that limit their use. Herein, the conversion of short peptide sequences into poly-α-amino-γ-lactam foldamers that adopt a ribbon-like structure is investigated. This template is used to distribute critical cationic and/or hydrophobic groups on both sides of the backbone, leading to potent short, cell-permeable foldamers with a low positive-charge content. The lead compound showed dramatically improved protease resistance and was able to efficiently deliver a biologically relevant cargo inside cells. This study provided a simple strategy to convert short peptide sequences into efficient protease-resistant cell-penetrating foldamers.

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“…The procedures are described in detail elsewhere [24][25][26]. Animals were anesthetized using 9% ± 1% desflurane in 30% oxygen and placed on a heat mat.…”

Section: Pet Scansmentioning

confidence: 99%

“…Several strategies have been reported to improve the low in vivo stability of CPPs [25]. One approach is simply to use the complementary version of the parent peptide built up from D-amino acids.…”

Section: Characterization Of the All-d Variant Of Sc18mentioning

confidence: 99%

Biological characterization of novel nitroimidazole‐peptide conjugates in vitro and in vivo

Bergmann

Splith

Pietzsch

et al. 2017

Journal of Peptide Science

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Recently, we reported on the design of a multimodal peptide conjugate useful as delivery platform for targeting hypoxic cells. A nitroimidazole (2-(2-nitroimidazol-1-yl)acetic acid, NIA) moiety, which is selectively entrapped in hypoxic cells, was coupled to a cell-penetrating peptide serving as the transporter. Furthermore, attachment of a bifunctional linker allowed the introduction of a diagnostic or therapeutic radiometal. However, although selective tumor accumulation could be detected in vivo, a fast renal clearance of the compound was observed. The present study aims to improve the system by using the more proteolytically stable all-d version of the peptide carrier (DsC18), by attaching two NIA moieties instead of one (DsC18(NIA) ) to enhance the tumor uptake, and by incorporating the bifunctional chelator NODAGA instead of DOTA (NODAGA-DsC18(NIA) ) to optimize labeling chemistry. First, we characterized in vitro the novel all-d peptide compared with its parent l-version. Then, in order to investigate and compare the pharmacological profiles of the peptides, these were radiolabeled with Cu and Ga , and the biodistribution and kinetics were evaluated in vivo. Our results show the versatility of the d-peptide as cell-penetrating peptide and transporter. However, attaching two NIA groups modified the system in such a way that no selective tumor uptake could be observed compared with the peptide without NIA moieties. Still, this work highlights new pharmacokinetic data on the biodistribution of such compounds in vivo. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Strategies to Stabilize Cell Penetrating Peptides forIn VivoApplications

Cited by 45 publications

References 197 publications

Study of the Antimicrobial Activity of Tilapia Piscidin 3 (TP3) and TP4 and Their Effects on Immune Functions in Hybrid Tilapia (Oreochromis spp.)

Study of the Antimicrobial Activity of Tilapia Piscidin 3 (TP3) and TP4 and Their Effects on Immune Functions in Hybrid Tilapia (Oreochromis spp.)

Ribbon‐like Foldamers for Cellular Uptake and Drug Delivery

Biological characterization of novel nitroimidazole‐peptide conjugates in vitro and in vivo

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