Penetratin and derivatives acting as antifungal agents

Masman, Marcelo F.; Rodrı́guez, Ana; Raimondi, Marcela; Zacchino, Susana; Luiten, P.G.M.; Somlai, Csaba; Körtvélyesi, Tamás; Penke, Botond; Enriz, Ricardo D.

doi:10.1016/j.ejmech.2008.02.019

Cited by 34 publications

(51 citation statements)

References 57 publications

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“…3 Small cationic peptides of this kind are important not only because they can penetrate cells but, additionally, some of them have been shown to possess antibiotic, 4 and/or antimicrobial properties. 5,6 The intriguing question since this discovery is: how can this highly cationic peptide (+7 charge) overcome the energetic barrier necessary to translocate into the lipid bilayer? Moreover, once inserted, how do the lipids in the membrane accommodate in presence of the strong electrostatic field generated by these charges?…”

Section: Introductionmentioning

confidence: 99%

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

General

Asciutto

2017

AIP Advances

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Penetratin belongs to the important class of small and positively charged peptides, capable of entering cells. The determination of the optimal peptidic structure for translocation is challenging; results obtained so far are varied and dependent on several factors. In this work, we review the dynamics of association of Penetratin with a modeled dioleoyl-phosphatidylcholine (DOPC) lipid membrane using molecular dynamics simulations with last generation force fields. Penetratin’s structural preferences are determined using a Markov state model. It is observed that the peptide retains a helical form in the membrane associated state, just as in water, with the exception of both termini which lose helicity, facilitating the interaction of terminal residues with the phosphate groups on the membrane’s outer layer. The optimal orientation for insertion is found to be with the peptide’s axis forming a small angle with the interface, and with R1 stretching toward the bilayer. The interaction between arginine side-chains and phosphate groups is found to be greater than the corresponding to lysine, mainly due to a higher number of hydrogen bonds between them. The free energy profile of translocation is qualitatively studied using Umbrella Sampling. It is found that there are different paths of penetration, that greatly differ in size of free energy barrier. The lowest path is compatible with residues R10 to K13 leading the way through the membrane and pulling the rest of the peptide. When the other side is reached, the C-terminus overtakes those residues, and finally breaks out of the membrane. The peptide’s secondary structure during this traversal suffers some changes with respect to the association structure but, overall, conserves its helicity, with both termini in a more disordered state.

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Section: Introductionmentioning

confidence: 99%

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

General

Asciutto

2017

AIP Advances

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“…The minimization was performed using the Amber14SB force field imposing a wick backbone atoms restraint of 0.5 Kcal/mol/Å. After the above energy minimization stage, the minimized complexes were subjected to quantum mechanics (QM) calculations at the PM7 semiempirical molecular orbital method to obtain the binding energy including the COSMO Solvation method . Binding enthalpy for the EspA‐ligand complexes were calculated in accordance with the following equation:

{∆H}_{binding} = {∆H}_{EspA - Ligand} - ((), {∆H}_{EspA} + {∆H}_{Ligand})

Where ∆H EspA − Ligand = calculated enthalpy of formation of the EspA‐ligand complex.…”

Section: Methodsmentioning

confidence: 99%

An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli

Larzábal

Baldoni

Suvire

et al. 2019

Journal of Peptide Science

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Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern.

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“…Immune compromise can be because of ailments such as AIDS, azotemia, diabetes mellitus, neoplastic disease, lymphoma, leukemia, other hematologic cancers, burns and therapy with corticosteroids, antibiotics, immune-suppressants, or anti-metabolites. Patients who spend more than several days in an ICU can become immunecompromised because of undergoing blood and marrow transplantation (BMT), solid-organ transplantation, and major surgery (especially gastrointestinal surgery) [11][12][13][14] . 26 .…”

Section: Methodsmentioning

confidence: 99%

Untitled

2017

IJPSR

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Statistical figures represent that fungal infections are the major cause of thousands of deaths each year. Despite the availability of treatment options invasive and systemic fungal infections have alarmingly higher mortality rates. This current review tabulates such fungal organisms that are pathogenic and fatal to human. This article provides a compilation of all Mycoses in human and also reports about the risk group of each fungus based on which, the level of risk caused by fungi can be determined. Infections caused by Dimorphic fungal pathogens (Blastomyces, Coccidioides, Marneffei) and Dematiaceous hyphomycetes (Cladophialophora, Rhinocladiella) belong to major fatal causing risk group 3 resulting in higher death rates of individuals. It also reports about various types of possible classification of mycoses i.e. based on reaction of human to fungi, host susceptibility, pathogen type, body location and risk group. The article highlights the estimated incidence of fungal diseases due to these pathogens, but these statistical figures are usually underestimated so there is a great need for advancement in understanding of fungus, their resistance along with immunity reports. In order to meet all these disease combating requirements, many high quality research initiatives with proper sources of funding and encouragement have to be provided. Article also reviews the major antifungal drugs available along with their brief pharmacokinetic profile. It also briefs some take home remedies in order to prevent and treat major fungal infection along with the alternative and novel modelling techniques developed recently for drug designing to target various development stages of fungal organism.

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Penetratin and derivatives acting as antifungal agents

Cited by 34 publications

References 57 publications

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli

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