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Special Issue "State of the Art of Membrane Active Peptides"

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 30 November 2023 | Viewed by 9589

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Dr. Corina Ciobanasu

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Department of Exact and Natural Sciences, Institute of Interdisciplinary Research, Alexandru I. Cuza University, Blvd. Carol I, No. 11, 700506 Iasi, Romania
Interests: cell penetrating peptides; antimicrobial peptides; fluorescence microscopy; molecular interactions; biomimetic systems; drug delivery systems

Dr. Brînduşa Alina Petre

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1. Faculty of Chemistry, Al. I. Cuza University of Iasi, 11, Carol I Boulevard, 700506 Iasi, Romania
2. Department of Chemistry & Biomolecular Science, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699, USA
3. Center for Fundamental Research and Experimental Development in Translation Medicine–TRANSCEND, Regional Institute of Oncology, 700483 Iasi, Romania
Interests: peptide chemistry; amyloid peptides; mass spectrometry; proteomics; enzymatic substrates; lysosomal rare diseases
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Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to the Special Issue “State-of-the-Art of Membrane-Active Peptides”. This issue is focused on membrane-active peptides that interact with the cell membrane and exert their biological activity by delivering different molecules inside cells or by disrupting the membrane followed cell lysis. Cell-penetrating peptides (CPPs) surmount the membrane barrier and deliver a great number of cargoes into the cells. CPPs act by the direct translocation of the membrane, pore formation or by endocytic routes. Antimicrobial peptides (AMPs) are components of the innate immunity and serve as first line protection against pathogens. Nowadays, multidrug-resistant bacteria to available antibiotics represent a major challenge, and AMPs are used to create a new generation of antibacterial drugs. Antimicrobial peptides target the bacterial membrane and lyse it using different mechanisms, such as the toroidal pore, the carpet model or the barrel stave model. Membrane-active peptides are considered as promising alternatives to current pharmaceuticals. However, their therapeutic potential is restricted by the current understanding of their molecular mechanism of action.

This Special Issue aims to bring together the latest advances regarding the molecular mechanism of peptide internalization, techniques to reveal these modes of peptide uptake and develop new peptide sequences, biological activity, applications and clinical data.

In this Special Issue, original research articles and reviews are welcome. Research areas may include, but are not limited to, the following:

Molecular mechanisms of membrane-active peptides;
Techniques to reveal the molecular mechanisms of membrane-active peptides;
Recent advances in applications of membrane-active peptides in biotechnology and medicine;
New peptide sequences and their biological activity;
Drug delivery systems based on membrane-active peptides.

We look forward to receiving your contributions.

Dr. Corina Ciobanasu
Dr. Brînduşa Alina Petre
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cell-penetrating peptides
antimicrobial peptides
homing peptides
drug delivery system
cellular internalization
nanoparticles
cellular targeting
therapeutics
diagnostics

Published Papers (10 papers)

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Open AccessArticle

Relating Molecular Dynamics Simulations to Functional Activity for Gly-Rich Membranolytic Helical Kiadin Peptides

and

Pharmaceutics 2023, 15(5), 1433; https://doi.org/10.3390/pharmaceutics15051433 - 08 May 2023

Viewed by 615

Abstract

Kiadins are in silico designed peptides with a strong similarity to diPGLa-H, a tandem sequence of PGLa-H (KIAKVALKAL) and with single, double or quadruple glycine substitutions. They were found to show high variability in their activity and selectivity against Gram-negative and Gram-positive bacteria, as well as cytotoxicity against host cells, which are influenced by the number and placing of glycine residues along the sequence. The conformational flexibility introduced by these substitutions contributes differently peptide structuring and to their interactions with the model membranes, as observed by molecular dynamics simulations. We relate these results to experimentally determined data on the structure of kiadins and their interactions with liposomes having a phospholipid membrane composition similar to simulation membrane models, as well as to their antibacterial and cytotoxic activities, and also discuss the challenges in interpreting these multiscale experiments and understanding why the presence of glycine residues in the sequence affected the antibacterial potency and toxicity towards host cells in a different manner. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Adjusting Heterodimeric Coiled-Coils (K/E Zipper) to Connect Autophagy-Inducing Peptide with Cell-Penetrating Peptide

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Pharmaceutics 2023, 15(4), 1048; https://doi.org/10.3390/pharmaceutics15041048 - 24 Mar 2023

Viewed by 508

Abstract

A connection of a functional peptide with a cell-penetrating peptide (CPP) used a heterodimeric coiled-coil as a molecular zipper can improve the intracellular delivery and activity of the functional peptide. However, the chain length of the coiled coil required for functioning as the molecular zipper is unknown at present. To solve the problem, we prepared an autophagy-inducing peptide (AIP) that conjugates with the CPP via heterodimeric coiled-coils consisting of 1 to 4 repeating units (K/E zipper; AIP-Kn and En-CPP), and we investigated the optimum length of the K/E zipper for effective intracellular delivery and autophagy induction. Fluorescence spectroscopy showed that K/E zippers with n = 3 and 4 formed a stable 1:1 hybrid (AIP-K3/E3-CPP and AIP-K4/E4-CPP, respectively). Both AIP-K3 and AIP-K4 were successfully delivered into cells by the corresponding hybrid formation with K3-CPP and K4-CPP, respectively. Interestingly, autophagy was also induced by the K/E zippers with n = 3 and 4, more intensively by the former than by the latter. The peptides and K/E zippers used in this study did not show significant cytotoxicity. These results indicate that the effective induction of autophagy occurs via an exquisite balance of the association and dissociation of the K/E zipper in this system. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessArticle

The Mechanism of Action of SAAP-148 Antimicrobial Peptide as Studied with NMR and Molecular Dynamics Simulations

Morgane Adélaïde

Evgeniy Salnikov

Francisco Ramos-Martín

Christopher Aisenbrey

Catherine Sarazin

Burkhard Bechinger

and

Nicola D’Amelio

Pharmaceutics 2023, 15(3), 761; https://doi.org/10.3390/pharmaceutics15030761 - 24 Feb 2023

Viewed by 867

Abstract

Background: SAAP-148 is an antimicrobial peptide derived from LL-37. It exhibits excellent activity against drug-resistant bacteria and biofilms while resisting degradation in physiological conditions. Despite its optimal pharmacological properties, its mechanism of action at the molecular level has not been explored. Methods: The structural properties of SAAP-148 and its interaction with phospholipid membranes mimicking mammalian and bacterial cells were studied using liquid and solid-state NMR spectroscopy as well as molecular dynamics simulations. Results: SAAP-148 is partially structured in solution and stabilizes its helical conformation when interacting with DPC micelles. The orientation of the helix within the micelles was defined by paramagnetic relaxation enhancements and found similar to that obtained using solid-state NMR, where the tilt and pitch angles were determined based on ¹⁵N chemical shift in oriented models of bacterial membranes (POPE/POPG). Molecular dynamic simulations revealed that SAAP-148 approaches the bacterial membrane by forming salt bridges between lysine and arginine residues and lipid phosphate groups while interacting minimally with mammalian models containing POPC and cholesterol. Conclusions: SAAP-148 stabilizes its helical fold onto bacterial-like membranes, placing its helix axis almost perpendicular to the surface normal, thus probably acting by a carpet-like mechanism on the bacterial membrane rather than forming well-defined pores. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessArticle

Mechanisms of a Mycobacterium tuberculosis Active Peptide

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Pharmaceutics 2023, 15(2), 540; https://doi.org/10.3390/pharmaceutics15020540 - 06 Feb 2023

Viewed by 744

Abstract

Multidrug-resistant tuberculosis (MDR) continues to pose a threat to public health. Previously, we identified a cationic host defense peptide with activity against Mycobacterium tuberculosis in vivo and with a bactericidal effect against MDR M. tuberculosis at therapeutic concentrations. To understand the mechanisms of this peptide, we investigated its interactions with live M. tuberculosis and liposomes as a model. Peptide interactions with M. tuberculosis inner membranes induced tube-shaped membranous structures and massive vesicle formation, thus leading to bubbling cell death and ghost cell formation. Liposomal studies revealed that peptide insertion into inner membranes induced changes in the peptides’ secondary structure and that the membranes were pulled such that they aggregated without permeabilization, suggesting that the peptide has a strong inner membrane affinity. Finally, the peptide targeted essential proteins in M. tuberculosis, such as 60 kDa chaperonins and elongation factor Tu, that are involved in mycolic acid synthesis and protein folding, which had an impact on bacterial proliferation. The observed multifaceted targeting provides additional support for the therapeutic potential of this peptide. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessArticle

A Diphenylalanine Based Pentapeptide with Fibrillating Self-Assembling Properties

Stefania-Claudia Jitaru

and

Vasile-Robert Gradinaru

Pharmaceutics 2023, 15(2), 371; https://doi.org/10.3390/pharmaceutics15020371 - 21 Jan 2023

Cited by 1 | Viewed by 1116

Abstract

Peptides and their related compounds can self-assemble into diverse nanostructures of different shapes and sizes in response to various stimuli such as pH, temperature or ionic strength. Here we report the synthesis and characterization of a lysozyme derived pentapeptide and its ability to build well-defined fibrillar structures. Lysozyme FESNF peptide fragment was synthesized by solid phase peptide synthesis using the Fmoc/t-Bu strategy, purified by analytical high-performance liquid chromatography (HPLC) and its molecular weight was confirmed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI–MS). Spectroscopic features of this pentapeptide were investigated by UV-visible spectroscopy and fluorimetry showing the pattern of marginal phenylalanine residues within the peptide sequence. Self-assembling properties were determined using atomic force microscopy (AFM), aggregation index and thioflavin T assay (ThT). FESNF generating fibrillar structures observed by AFM and aggregation propensity were primarily influenced by pH conditions. Moreover, the experimental data were confirmed by molecular dynamics simulation studies. The obtained fibrils will be used next to explore their potential to act as support material for medical and cosmetic application. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessFeature PaperArticle

Cell-Penetrating Dabcyl-Containing Tetraarginines with Backbone Aromatics as Uptake Enhancers

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Pharmaceutics 2023, 15(1), 141; https://doi.org/10.3390/pharmaceutics15010141 - 31 Dec 2022

Cited by 1 | Viewed by 904

Abstract

Cell-penetrating peptides represent an emerging class of carriers capable of effective cellular delivery. This work demonstrates the preparation and investigation of efficient CPPs. We have already shown that the presence of 4-((4-(dimethylamino)phenyl)azo)benzoic acid (Dabcyl) and Trp greatly increase the uptake of oligoarginines. This work is a further step in that direction. We have explored the possibility of employing unnatural, aromatic amino acids, to mimic Trp properties and effects. The added residues allow the introduction of aromaticity, not as a side-chain group, but rather as a part of the sequence. The constructs presented exceptional internalization on various cell lines, with an evident structure–activity relationship. The CPPs were investigated for their entry mechanisms, and our peptides exploit favorable pathways, yet one of the peptides relies highly on direct penetration. Confocal microscopy studies have shown selectivity towards the cell lines, by showing diffuse uptake in FADU cells, while vesicular uptake takes place in SCC-25 cell line. These highly active CPPs have proved their applicability in cargo delivery by successfully delivering antitumor drugs into MCF-7 and MDA-MB-231 cells. The modifications in the sequences allow the preparation of short yet highly effective constructs able to rival the penetration of well-known CPPs such as octaarginine (Arg8). Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessArticle

Antibacterial Potential Analysis of Novel α-Helix Peptides in the Chinese Wolf Spider Lycosa sinensis

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Pharmaceutics 2022, 14(11), 2540; https://doi.org/10.3390/pharmaceutics14112540 - 21 Nov 2022

Cited by 2 | Viewed by 817

Abstract

The spider Lycosa sinensis represents a burrowing wolf spider (family Lycosidae) widely distributed in the cotton region of northern China, whose venom is rich in various bioactive peptides. In previous study, we used a combination strategy of peptidomic and transcriptomic analyses to systematically screen and identify potential antimicrobial peptides (AMPs) in Lycosa sinensis venom that matched the α-helix structures. In this work, the three peptides (LS-AMP-E1, LS-AMP-F1, and LS-AMP-G1) were subjected to sequence analysis of the physicochemical properties and helical wheel projection, and then six common clinical pathogenic bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) with multiple drug-resistance were isolated and cultured for the evaluation and analysis of antimicrobial activity of these peptides. The results showed that two peptides (LS-AMP-E1 and LS-AMP-F1) had different inhibitory activity against six clinical drug-resistant bacteria; they can effectively inhibit the formation of biofilm and have no obvious hemolytic effect. Moreover, both LS-AMP-E1 and LS-AMP-F1 exhibited varying degrees of synergistic therapeutic effects with traditional antibiotics (azithromycin, erythromycin, and doxycycline), significantly reducing the working concentration of antibiotics and AMPs. In terms of antimicrobial mechanisms, LS-AMP-E1 and LS-AMP-F1 destroyed the integrity of bacterial cell membranes in a short period of time and completely inhibited bacterial growth within 10 min of action. Meanwhile, high concentrations of Mg²⁺ effectively reduced the antibacterial activity of LS-AMP-E1 and LS-AMP-F1. Together, it suggested that the two peptides interact directly on bacterial cell membranes. Taken together, bioinformatic and functional analyses in the present work sheds light on the structure–function relationships of LS-AMPs, and facilitates the discovery and clinical application of novel AMPs. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessArticle

Heterogeneous Structural Disturbance of Cell Membrane by Peptides with Modulated Hydrophobic Properties

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Pharmaceutics 2022, 14(11), 2471; https://doi.org/10.3390/pharmaceutics14112471 - 15 Nov 2022

Viewed by 639

Abstract

Extensive effort has been devoted to developing new clinical therapies based on membrane-active peptides (MAPs). Previous models on the membrane action mechanisms of these peptides mostly focused on the MAP–membrane interactions in a local region, while the influence of the spatial heterogeneity of the MAP distribution on the membrane was much ignored. Herein, three types of natural peptide variants, AS4-1, AS4-5, and AS4-9, with similar amphiphilic α-helical structures but distinct hydrophobic degrees (AS4-1 < AS4-5 < AS4-9) and net charges (+9 vs. +7 vs. +5), were used to interact with a mixed phosphatidylcholine (PC) and phosphatidylglycerol (PG) membrane. A combination of giant unilamellar vesicle (GUV) leakage assays, atomic force microscopy (AFM) characterizations, and molecular dynamics (MD) simulations demonstrated the coexistence of multiple action mechanisms of peptides on a membrane, probably due to the spatially heterogeneous distribution of peptides on the membrane surface. Specifically, the most hydrophobic peptide (i.e., AS4-9) had the strongest membrane binding, perturbation, and permeabilization effects, leading to the formation of large peptide–lipid aggregates (10 ± 5 nm in height and 150 ± 50 nm in size), as well as continuous fragments and ridges on the supported membrane surface. The AS4-5 peptides, with a half-hydrophilic and half-hydrophobic structure, induced membrane lysis in addition to reconstruction. The most hydrophilic peptide AS4-1 only exhibited unstable binding on the supported membrane surface. These results demonstrate the heterogeneous structural disturbance of model cell membranes by amphiphilic α-helical peptides, which could be significantly strengthened by increasing the degree of hydrophobicity and/or local number density of peptides. This work provides support for the modulation of the membrane activity of MAPs by adjusting their hydrophobicity and local concentration. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Open AccessArticle

Confocal Laser Scanning Microscopy and Model Membranes to Study Translocation Mechanisms of Membrane Active Peptides

Corina Ciobanasu

Pharmaceutics 2022, 14(8), 1699; https://doi.org/10.3390/pharmaceutics14081699 - 15 Aug 2022

Viewed by 965

Abstract

Membrane active peptides hold great potential for targeted drug delivery systems and understanding their mechanism of uptake is a key step in the development of peptide based therapeutics and clinical use. Giant unilamellar vesicles are cell-sized model membranes that can be individually observed under the microscope. The lipid composition of these membranes can be controlled, and interaction with peptides and changes induced by the peptides can be directly followed. Relevant information on the specific steps of peptides uptake can be obtained using membranes of different lipid composition. The present work provides a selection of dynamics and kinetics of peptides at interaction with model membranes of different lipid composition. The systematic peptide-membrane interaction was investigated by laser scanning confocal microscopy. The peptides used in this study neither internalized nor induced pore formation in neutral membranes composed of phosphatidylcholine and cholesterol. In membranes with anionic phosphatidylserine or cone-shaped phosphatidylethanolamine, all peptides internalized but only two of them were able to form pores, showing that the length of the peptide, the numbers of the arginine amino acid or the length of the α–helix are also relevant for the penetration efficiency of peptides. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies

Saeed Anwar

Farin Mir

and

Toshifumi Yokota

Pharmaceutics 2023, 15(4), 1130; https://doi.org/10.3390/pharmaceutics15041130 - 03 Apr 2023

Viewed by 1338

Abstract

Oligonucleotide-based therapies are a promising approach for treating a wide range of hard-to-treat diseases, particularly genetic and rare diseases. These therapies involve the use of short synthetic sequences of DNA or RNA that can modulate gene expression or inhibit proteins through various mechanisms. Despite the potential of these therapies, a significant barrier to their widespread use is the difficulty in ensuring their uptake by target cells/tissues. Strategies to overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, and the use of endogenous vesicles, spherical nucleic acids, and smart material-based delivery vehicles. This article provides an overview of these strategies and their potential for the efficient delivery of oligonucleotide drugs, as well as the safety and toxicity considerations, regulatory requirements, and challenges in translating these therapies from the laboratory to the clinic. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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