Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs.
Ontology highlight
ABSTRACT:
SUBMITTER: Bellavita R
PROVIDER: S-EPMC7534258 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides' characteristics and current applications in immunomodulatory therapeutics.
| S-EPMC10014862 | biostudies-literature
Project description:A novel approach for boosting antimicrobial peptides through end tagging with hydrophobic oligopeptide stretches is demonstrated. Focusing on two peptides derived from kininogen, GKHKNKGKKNGKHNGWK (GKH17) and HKHGHGHGKHKNKGKKN (HKH17), tagging resulted in enhanced killing of Gram-positive Staphylococcus aureus, Gram-negative Escherichia coli, and fungal Candida albicans. Microbicidal potency increased with tag length, also in plasma, and was larger for Trp and Phe stretches than for aliphatic ones. The enhanced microbicidal effects correlated to a higher degree of bacterial wall rupture. Analogously, tagging promoted peptide binding to model phospholipid membranes and liposome rupture, particularly for anionic and cholesterol-void membranes. Tagged peptides displayed low toxicity, particularly in the presence of serum, and resisted degradation by human leukocyte elastase and by staphylococcal aureolysin and V8 proteinase. The biological relevance of these findings was demonstrated ex vivo and in vivo in porcine S. aureus skin infection models. The generality of end tagging for facile boosting of antimicrobial peptides without the need for post-synthesis modification was also demonstrated.
| S-EPMC2719397 | biostudies-literature
Project description:Rapid spread of antibiotic resistance throughout the kingdom bacteria is inevitably bringing humanity towards the "post-antibiotic" era. The emergence of so-called "superbugs"-pathogen strains that develop resistance to multiple conventional antibiotics-is urging researchers around the globe to work on the development or perfecting of alternative means of tackling the pathogenic bacteria infections. Although various conceptually different approaches are being considered, each comes with its advantages and drawbacks. While drug-resistant pathogens are undoubtedly represented by both Gram(+) and Gram(-) bacteria, possible target spectrum across the proposed alternative approaches of tackling them is variable. Numerous anti-virulence strategies aimed at reducing the pathogenicity of target bacteria rather than eliminating them are being considered among such alternative approaches. Sortase A (SrtA) is a membrane-associated cysteine protease that catalyzes a cell wall sorting reaction by which surface proteins, including virulence factors, are anchored to the bacterial cell wall of Gram(+) bacteria. Although SrtA inhibition seems perspective among the Gram-positive pathogen-targeted antivirulence strategies, it still remains less popular than other alternatives. A decrease in virulence due to inactivation of SrtA activity has been extensively studied in Staphylococcus aureus, but it has also been demonstrated in other Gram(+) species. In this manuscript, results of past studies on the discovery of novel SrtA inhibitory compounds and evaluation of their potency were summarized and commented on. Here, we discussed the rationale behind the inhibition of SrtA, raised some concerns on the comparability of the results from different studies, and touched upon the possible resistance mechanisms as a response to implementation of such therapy in practice. The goal of this article is to encourage further studies of SrtA inhibitory compounds.
| S-EPMC7916047 | biostudies-literature
Project description:Lipidised analgesic peptide prodrugs self-assemble into peptide nanofibers; with the nanofiber morphology protecting the peptide from plasma degradation and improving therapeutic efficacy. Extending this learning, we hypothesised that a self-assembling lipidized peptide arginine vasopressin (AVP) receptor agonist, that had not been designed as a prodrug, could prove pharmacologically active and control urine production. The only approved AVP receptor agonist, desmopressin is indicated for the treatment of central diabetes insipidus (DI), bedwetting, haemophilia A and von Willebrand disease. Desmopressin is well tolerated by most patients, however adverse effects, such as hyponatraemia and water intoxication necessitate a strict fluid intake, thus motivating the search for alternative DI treatments. Selective V2 receptor agonism is required for anti-DI activity and we hypothesised that our new lipidized peptide (METx) would lead to selective AVP receptor agonism. METx was synthesised and characterised and then tested for activity against the V2, V1a and OT uterine receptors and not tested against the V1b receptor as METx was not expected to cross the blood brain barrier. METx was also tested in vivo in a healthy rat model. METx forms nanofibers and is a partial V2 receptor agonist (determined by measuring MDCK cell line cAMP accumulation), producing 57% of AVP's maximal activity (EC50 = 2.7 nM) and is not a V1a agonist up to a concentration of 1 μM (determined by measuring A7r5 cell line D-myo-inositol-1-phosphate accumulation). METx is a weak OT receptor antagonist, reducing the frequency of OT induced contractions (EC50 = 350 nM) and increasing the OT EC50 from 0.081 nM to 21 nM at a concentration of 600 nM. METx (41 nM) had no effect on spontaneous uterine contractions and METx (100 nM) had no effect on OT induced uterine contractions. Simulated binding studies show that binding avidity to the receptors follows the trend: V2 > OT > V1a. On intravenous injection, a nanoparticle formulation of METx reduced urine production in a healthy rat model in a dose responsive manner, with 40 mg kg-1 METx resulting in no urine production over 4 hours. The lipidized self-assembling peptide - METx - is a selective competitive V2 receptor agonist and an anti-diuretic.
| S-EPMC7190706 | biostudies-literature
Project description:Fluorescent hydrogels (FH) have a variety of potential applications in the field of soft electronics. However, fabrication of mechanically stable and printable fluorescent hydrogels remains challenging. Here, we report a kind of fluorescent hydrogel based on the co-assembly of peptide motif and transition metal ions. The metal ions are captured in the hydrogel network at specific positions through covalently linked ligands on the peptide hydrogelators. This efficiently prevents the aggregation and self-quenching of organometallic chromophores. In addition, the formation of metal-ligand complexes introduces additional interactions to stabilize the hydrogel network, making the FH even more stable after the incorporation of metal ions. The FH is optically transparent but highly fluorescent. By using three different metal ions, the white light fluorescent supramolecular hydrogel has been achieved. As a proof-of-principle, we demonstrate the printability of the hydrogels to various patterns. We anticipate that with the improved fluorescent performance and stability, this kind of FH can find broad applications in extrusion-based 3D printing for the construction of soft electronics.
| S-EPMC5574881 | biostudies-other
Project description:High levels of serum low-density lipoprotein (LDL) cholesterol contribute to atherosclerosis, a key risk factor of cardiovascular diseases. PCSK9 is a circulatory enzyme that downregulates expression of hepatic LDL receptors, concomitantly increasing serum LDL-C. This work investigates a small, self-assembling peptide, EPep2-8, as a peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8, previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular β-sheet secondary structure. Intermolecular interactions between nanofibers drive EPep2-8 to form a thixotropic and cytocompatible hydrogel in aqueous and charge-neutral solutions. These properties enable EPep2-8 to be delivered as an in situ depot for regulation of lipoprotein homeostasis. In surface plasmon resonance studies, EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent, and irreversible dissociation, significantly improving the binding affinity of Pep2-8 alone (KD = 667 ± 48 nM). Increased binding affinity of EPep2-8 is primarily due to the superstoichiometric interaction of the peptide with PCSK9. Promisingly, EPep2-8 retains bioactivity in vitro, engendering dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly on a target site may be a simple method to improve the affinity of peptide inhibitors.
| S-EPMC10790182 | biostudies-literature
Project description:In our previous study, temporin-GHaR (GHaR) showed potent antimicrobial activity with strong hemolytic toxicity. To overcome its weakness, we designed GHaR6R, GHaR7R, GHaR8R, GHaR9R, and GHaR9W by changing the number of positive charges and the hydrophobic surface of GHaR. With the exception of GHaR7R, the hemolytic toxicity of the derived peptides had been reduced, and the antimicrobial activities remained close to the parent peptide (except for GHaR9R). GHaR6R, GHaR7R, GHaR8R, and GHaR9W exhibited a great bactericidal effect on Streptococcus mutans (S. mutans), which is one of the main pathogens causing dental caries. According to the membrane permeation and scanning electron microscope (SEM) analysis, these derived peptides targeted to the cell membranes of planktonic bacteria, contributing to the disruption of the membrane integrity and leakage of the intracellular contents. Moreover, they inhibited the formation of biofilms and eradicated the mature biofilms of S. mutans. Compared with GHaR7R, the derived peptides showed less cytotoxicity to human oral epithelial cells (HOECs). The derived peptides are expected to be the molecular templates for designing antibacterial agents to prevent dental caries.
| S-EPMC7730238 | biostudies-literature
Project description:Temporins are a family of antimicrobial peptides (AMPs) isolated from frog skin, which are very short, weakly charged, and highly hydrophobic. They execute bactericidal activities in different ways from many other AMPs. This work investigated morphological changes of planar bilayer membranes composed of mixed zwitterionic and anionic phospholipids induced by temporin B and L (TB and TL) using all-atom and coarse-grained molecular dynamics simulations. We found that TB and TL fold to α-helices at the membrane surface and penetrate shallowly into the bilayer. These short AMPs have low propensity to induce membrane pore formation but possess high ability to extract lipids out. At relatively high peptide concentrations, the strong hydrophobicity of TB and TL promotes them to aggregate into clusters on the membrane surface. These aggregates attract a large amount of lipids out of the membrane to release compression induced by other dispersed peptides binding to the membrane. The extruded lipids mix evenly with the peptides in the cluster and form tubule-like protrusions. Certain water molecules follow the movement of lipids, which not only fill the cavities of the protrusion but also assist in maintaining the tubular structures. In contrast, the peptide-free leaflet remains intact. The present results unravel distinctive antimicrobial mechanisms of temporins disturbing membranes.
| S-EPMC8537239 | biostudies-literature
Project description:Regenerative medicine holds great potential to address many shortcomings in current medical therapies. An emerging avenue of regenerative medicine is the use of self-assembling peptides (SAP) in conjunction with stem cells to improve the repair of damaged tissues. The specific peptide sequence, mechanical properties, and nanotopographical cues vary widely between different SAPs, many of which have been used for the regeneration of similar tissues. To evaluate the potential of SAPs to guide stem cell fate, we extensively reviewed the literature for reports of SAPs and stem cell differentiation. To portray the most accurate summary of these studies, we deliberately discuss both the successes and pitfalls, allowing us to make conclusions that span the breadth of this exciting field. We also expand on these conclusions by relating these findings to the fields of nanotopography, mechanotransduction, and the native composition of the extracellular matrix in specific tissues to identify potential directions for future research.
| S-EPMC4803621 | biostudies-literature
Project description:Hydrogel materials that display inherent activity against bacteria can be used to directly treat accessible wounds to prevent or kill existing infection. Hydrogels composed of self-assembling ?-hairpin peptides, having a high content of arginine, were found to be extremely effective at killing both gram-positive and gram-negative bacteria, including multi-drug resistant Pseudomonas aeruginosa. No added antibacterial agents are necessary to realize activity. Using self-assembling peptides for material construction allows facile structure-activity relationships to be determined since changes in peptide sequence at the monomer level are directly transposed to the bulk material's antibacterial properties. SAR studies show that arginine content largely influences the hydrogel's antibacterial activity, and influences their bulk rheological properties. These studies culminated in an optimized gel, composed of the peptide PEP6R (VKVRVRVRV(D)PPTRVRVRVKV). PEP6R gels prepared at 1.5 wt % or higher concentration, demonstrate high potency against bacteria, but are cytocompatible toward human erythrocytes as well as mammalian mesenchymal stem cells. Rheological studies indicate that the gel is moderately stiff and displays shear-thin recovery behavior, allowing its delivery via simple syringe.
| S-EPMC3466390 | biostudies-literature