New Conjugates of Vancomycin with Cell-Penetrating Peptides-Synthesis, Antimicrobial Activity, Cytotoxicity, and BBB Permeability Studies.

Vancomycin (Van) is a glycopeptide antibiotic commonly used as a last resort for treating life-threatening infections caused by multidrug-resistant bacterial strains, such as and spp. However, its effectiveness is currently limited due to the rapidly increasing number of drug-resistant clinical strains and its inherent cytotoxicity and poor penetration into cells and specific regions of the body, such as the brain. One of the most promising strategies to enhance its efficacy appears to be the covalent attachment of cell-penetrating peptides (CPPs) to the Van structure.

Solid Phase Synthesis and TAR RNA-Binding Activity of Nucleopeptides Containing Nucleobases Linked to the Side Chains via 1,4-Linked-1,2,3-triazole.

Nucleopeptides (NPs) represent synthetic polymers created by attaching nucleobases to the side chains of amino acid residues within peptides. These compounds amalgamate the characteristics of peptides and nucleic acids, showcasing a unique ability to recognize RNA structures. In this study, we present the design and synthesis of Fmoc-protected nucleobase amino acids (1,4-TzlNBAs) and a new class of NPs, where canonical nucleobases are affixed to the side chain of -homoalanine (Hal) through a 1,4-linked-1,2,3-triazole (HalTzl).

The Application of Peptide Nucleic Acids (PNA) in the Inhibition of Proprotein Convertase Subtilisin/Kexin 9 () Gene Expression in a Cell-Free Transcription/Translation System.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis.

Structure-Activity Relationship of New Chimeric Analogs of Mastoparan from the Wasp Venom .

Mastoparan (MP) is an antimicrobial cationic tetradecapeptide with the primary structure INLKALAALAKKIL-. This amphiphilic α-helical peptide was originally isolated from the venom of the wasp . MP shows a variety of biological activities, such as inhibition of the growth of Gram-positive and Gram-negative bacteria, as well as hemolytic activity and activation of mast cell degranulation.

Interaction of Arginine-Rich Cell-Penetrating Peptides with an Artificial Neuronal Membrane.

Arginine-rich cell-penetrating peptides (RRCPPs) exhibit intrinsic neuroprotective effects on neurons injured by acute ischemic stroke. Conformational properties, interaction, and the ability to penetrate the neural membrane are critical for the neuroprotective effects of RRCCPs. In this study, we applied circular dichroism (CD) spectroscopy and coarse-grained molecular dynamics (CG MD) simulations to investigate the interactions of two RRCPPs, Tat(49-57)-NH (arginine-rich motif of Tat HIV-1 protein) and PTD4 (a less basic Ala-scan analog of the Tat peptide), with an artificial neuronal membrane (ANM).

Publisher Correction: Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Epigenetic inhibitor zebularine activates ear pinna wound closure in the mouse.

Background: Most studies on regenerative medicine focus on cell-based therapies and transplantations. Small-molecule therapeutics, though proved effective in different medical conditions, have not been extensively investigated in regenerative research. It is known that healing potential decreases with development and developmental changes are driven by epigenetic mechanisms, which suggests epigenetic repression of regenerative capacity.

Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin.

In the presented study, transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain. The antibacterial activity of the conjugates was tested on selected clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus sp. It turned out that all of them had superior antimicrobial activity in comparison to that of free Van, which became visible particularly against clinical MRSA strains.

TP10-Dopamine Conjugate as a Potential Therapeutic Agent in the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder for which the current treatment is not fully satisfactory. One of the major drawbacks of current PD therapy is poor penetration of drugs across the blood-brain barrier (BBB). In recent years, cell-penetrating peptides (CPPs) such as Tat, SynB, or TP10 have gained great interest due to their ability to penetrate cell membranes and to deliver different cargos to their targets including the central nervous system (CNS).

Capillary electrophoresis study of systemin peptides spreading in tomato plant.

Systemin (Sys) is an 18-aa plant peptide hormone involved in the regulation of plant's defensive response. Sys is considered as a fast-spreading systemic wound signal. We developed a simple and rapid CE method to monitor the spreading of Sys peptides through tomato plant.

Monitoring the Transcriptional Activity of Human Endogenous Retroviral HERV-W Family Using PNA Strand Invasion into Double-Stranded DNA.

In the presented assay, we elaborated a method for distinguishing sequences that are genetically closely related to each other. This is particularly important in a situation where a fine balance of the allele abundance is a point of research interest. We developed a peptide nucleic acid (PNA) strand invasion technique for the differentiation between multiple sclerosis-associated retrovirus (MSRV) and ERVWE1 sequences, both molecularly similar, belonging to the human endogenous retrovirus HERV-W family.

The application of strand invasion phenomenon, directed by peptide nucleic acid (PNA) and single-stranded DNA binding protein (SSB) for the recognition of specific sequences of human endogenous retroviral HERV-W family.

The HERV-W family of human endogenous retroviruses represents a group of numerous sequences that show close similarity in genetic composition. It has been documented that some members of HERV-W-derived expression products are supposed to play significant role in humans' pathology, such as multiple sclerosis or schizophrenia. Other members of the family are necessary to orchestrate physiological processes (eg, ERVWE1 coding syncytin-1 that is engaged in syncytiotrophoblast formation).

A Novel, Highly Selective RT-QPCR Method for Quantification of MSRV Using PNA Clamping Syncytin-1 (ERVWE1).

HERV-W is a multi-locus family of human endogenous retroviruses (HERVs) that has been found to play an important role in human physiology and pathology. Two particular members of HERV-W family are of special interests: ERVWE1 (coding syncytin-1, which is a glycoprotein essential in the formation of the placenta) and MSRV (multiple sclerosis-associated retrovirus that is thought to play a significant role in human pathology as a result of its increased expression in the brain tissue and blood cells derived from patients with multiple sclerosis (MS)). Both ERVWE1 and MSRV mRNA share high level of similarity and hence a method that allows to exclusively quantify the MSRV expression in clinical samples would be desirable.

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells.

Many biologically active compounds, including macromolecules that are used as various kinds of drugs, must be delivered to the interior of cell or organelles such as mitochondria or nuclei to achieve a therapeutic effect. However, very often, lipophilic cell membrane is impermeable for these molecules. A new method in the transport of macromolecules through the cell membrane is the one based on utilizing cell-penetrating peptides (CPPs).

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines.

Introduction: Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot).

'Click' chemistry synthesis and capillary electrophoresis study of 1,4-linked 1,2,3-triazole AZT-systemin conjugate.

The Cu(I) catalyzed Huisgen 1,3-dipolar azide-alkyne cycloaddition (CuAAC) was applied for a nucleoside-peptide bioconjugation. Systemin (Sys), an 18-aa plant signaling peptide naturally produced in response to wounding or pathogen attack, was chemically synthesized as its N-propynoic acid functionalized analog (Prp-Sys) using the SPPS. Next, CuAAC was applied to conjugate Prp-Sys with 3'-azido-2',3'-dideoxythymidine (AZT), a model cargo molecule.

A peptide nucleic acid (PNA)-mediated polymerase chain reaction clamping allows the selective inhibition of the ERVWE1 gene amplification.

A new peptide nucleic acid (PNA) mediated QPCR technique for the detection and quantification of the Multiple Sclerosis-Associated Retrovirus (MSRV) belonging to the human endogenous retrovirus-W (HERV-W) family has been developed. The assay utilizes a PNA probe which is fully complementary to the ERVWE1 sequence, another member of the HERV-W family which is closely related to MSRV. Due to its excellent affinity to a completely matched template, PNA probe selectively blocks the amplification of ERVWE1 thus allowing the specific and exclusive detection and quantification of the MSRV as PNA does not interfere with the amplification of MSRV.

Synthesis and hybridization studies of a new CPP-PNA conjugate as a potential therapeutic agent in atherosclerosis treatment.

The objective of this study was to design and synthesize a new CPP-PNA conjugate that would be able to penetrate endothelial cells, bind STAT1 mRNA and thereby block the activity of STAT1 (the Signal Transducer and Activator of Transcription 1), which is important in cases of vessel inflammation. In the course of the study, the TAMRA-PTD-4- Hal(traziole-Gly-PNA)-conjugate was successfully synthesized using a specific 1,3-dipolar Huisgen cycloaddition reaction known as a "click reaction". The hybridization properties of the conjugate to complementary hSTAT1 mRNA and hSTAT1 ssDNA fragments was verified by capillary electrophoresis (CE).

Cell-penetrating peptides modulate the vascular action of phenylephrine.

Cell-penetrating peptides (CPP) are a family of peptides able to penetrate the cell membrane. This group of compounds has attracted consideration as potential therapeutic tools for the delivery of various substances into cells. Here, we investigated possible interactions between several CPP synthesized in our laboratory and the vascular action of phenylephrine.

Aspartimide modified galanin analogue antagonizes galanin action on insulin secretion.

Aspartimide (Asi) formation is one of the most serious side reactions that can occur both during solid phase synthesis and storage of peptides containing aspartic acid. Although numerous studies on the mechanism of Asi formation conducted so far, the problem still remains unresolved and relatively little is known about the impact of this side reaction on biological properties of such modified peptides. In the present work we characterized the effect of Asi formation on biological properties of galanin(1-15) analogue modified in position 14 with aspartic acid, investigating its action on rat isolated gastric smooth muscles and glucose-induced insulin secretion from rat isolated islets of Langerhans.

New galanin(1-15) analogues modified in positions 9, 10 and 11 act as galanin antagonists on glucose-induced insulin secretion.

Galanin (GAL) is a 29-amino-acid residue peptide originally isolated from porcine upper small intestine. GAL exhibits various physiological activities, such as effects on hormones release, smooth muscles contractions, gastric acid secretion, neurons degeneration and feeding. One of the biological actions of GAL is the inhibition of insulin secretion from the pancreatic beta-cells.

Problem of aspartimide formation in Fmoc-based solid-phase peptide synthesis using Dmab group to protect side chain of aspartic acid.

The sequence-dependent, acid- or base-catalysed aspartimide formation is one of the most serious side reactions in solid-phase synthesis of peptides containing aspartic acid. In the present work, we investigated the susceptibility of 4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl (Dmab), an aspartic acid beta-carboxy side-chain protecting group, for aspartimide formation. As a model, 15-amino acid-residue galanin fragment analogue containing the Asp-Ala motif was used during Fmoc-based solid-phase synthesis.

Synthesis and biological properties of new chimeric galanin analogue GAL(1-13)-[Ala10,11]ET-1(6-21)-NH2.

Several chimeric peptides consisting of the N-terminal fragment of galanin (GAL) and C-terminal fragments of other bioactive peptides (e.g. substance P, bradykinin, neuropeptide Y, mastoparan) have been synthesized and reported as high-affinity galanin receptor antagonists.