Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant .

Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3-9 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality.

Structural Evaluation of Short Cationic Antimicrobial Peptides.

Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria.

Total synthesis of acylphloroglucinols and their antibacterial activities against clinical isolates of multi-drug resistant (MDR) and methicillin-resistant strains of Staphylococcus aureus.

Bioassay-directed drug discovery efforts focusing on various species of the genus Hypericum led to the discovery of a number of new acylphloroglucinols including (S,E)-1-(2-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-4,6-dihydroxyphenyl)-2-methylbutan-1-one (6, olympicin A) from H. olympicum, with MICs ranging from 0.5 to 1 mg/L against a series of clinical isolates of multi-drug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) strains.

Analogues of Disulfides from Allium stipitatum Demonstrate Potent Anti-tubercular Activities through Drug Efflux Pump and Biofilm Inhibition.

Disulfides from Allium stipitatum, commonly known as Persian shallot, were previously reported to possess antibacterial properties. Analogues of these compounds, produced by S-methylthiolation of appropriate thiols using S-methyl methanethiosulfonate, exhibited antimicrobial activity, with one compound inhibiting the growth of Mycobacterium tuberculosis at 17 µM (4 mg L) and other compounds inhibiting Escherichia coli and multi-drug-resistant (MDR) Staphylococcus aureus at concentrations ranging between 32-138 µM (8-32 mg L). These compounds also displayed moderate inhibitory effects on Klebsiella and Proteus species.

T-shaped Peptide Amphiphiles Self Assemble into Nanofiber Networks.

Background: Conventional nanofiber forming peptide amphiphiles comprise a beta sheet forming, short peptide sequence with an alkyl chain attached at one terminus. We report the selfassembly of a peptide amphiphile possessing a mid-chain located alkyl substituent (a T-shaped peptide amphiphile) into nanofiber networks.

Method: Peptide synthesis was carried out using standard 9-fluorenylmethoxycarbonyl solid phase peptide synthesis protocols, followed by covalent attachment of the alkyl chains to yield target peptide amphiphiles.

Synthesis and antibacterial evaluation of 3-Farnesyl-2-hydroxybenzoic acid from Piper multiplinervium.

3-Farnesyl-2-hydroxybenzoic acid is an antibacterial agent isolated from the leaves of Piper multiplinervium. This compound has activity against both Gram positive and Gram negative bacteria including Escherichia coli, Staphylococcus aureus and Helicobacter pylori. This research aimed to synthesize a natural antibacterial compound and its analogs.

A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus.

An in-depth evaluation was undertaken of a new antibacterial natural product (1) recently isolated and characterised from the plant Hypericum olympicum L. cf. uniflorum.

Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay.

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species.

Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database.

A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.

The oral use of neuropeptides to treat brain disease is currently not possible because of a combination of poor oral absorption, short plasma half-lives and the blood-brain barrier. Here we demonstrate a strategy for neuropeptide brain delivery via the (a) oral and (b) intravenous routes. The strategy is exemplified by a palmitic ester prodrug of the model drug leucine(5)-enkephalin, encapsulated within chitosan amphiphile nanoparticles.

Antibacterial acylphloroglucinols from Hypericum olympicum.

New antibacterial acylphloroglucinols (1-5) were isolated and characterized from the aerial parts of the plant Hypericum olympicum L. cf. uniflorum.

Bioactive pyridine-N-oxide disulfides from Allium stipitatum.

From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2'-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide.

DNA binding by analogues of the bifunctional intercalator TANDEM.

We have used DNase I footprinting to study the binding strength and DNA sequence selectivity of novel derivatives of the quinoxaline bis-intercalator TANDEM. Replacing the valine residues in the cyclic octadepsipeptide with lysines does not affect the selectivity for TpA but leads to a 50-fold increase in affinity. In contrast, replacing both of the quinoxaline chromophores with naphthalene rings abolishes binding, while changing a single ring decreases the affinity, and footprints are observed at only the best binding sites (especially TATATA).

Solid-phase synthesis of chlorofusin analogues.

We report an efficient and versatile solid-phase synthesis through which two series of chlorofusin analogues, one bearing varying chromophores and the other with various amino acid substitutions in the cyclic peptide, were synthesized. These peptides were prepared using a strategy involving side-chain immobilization, on-resin cyclization, and postcyclization modification. The success of these syntheses demonstrates the broad utility of the method.

Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies.

Echinomycin is the prototypical bisintercalator, a molecule that binds to DNA by inserting two planar chromophores between the base-pairs of duplex DNA, placing its cyclic depsipeptide backbone in the minor groove. As such, it has been the focus of an extensive number of investigations into its biological activity, nucleic acid binding and, to some extent, its structure-activity relationships. However, echinomycin is also the parent member of an extended family of natural products that interact with DNA by a similar mechanism of bisintercalation.

Efficient solid-phase-based total synthesis of the bisintercalator TANDEM.

[reaction: see text] In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue of triostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation, introduction of chromophores, and disulfide bond formation on the solid phase, prior to a final solution-phase macrolactamization, to give the target molecule. Although pure TANDEM was obtained in an overall yield comparable to those for all syntheses to date, the yield of the final cyclization was low (11%).

Solid-phase synthesis of the cyclic peptide portion of chlorofusin, an inhibitor of p53-MDM2 interactions.

The first solid-phase synthesis of the chlorofusin peptide is described. The synthesis involved side-chain immobilization of N(alpha)-Fmoc-Asp-ODmab. Synthesis of the linear peptide, initially incorporating racemic Ade8 and unsubstituted ornithine in place of the chromophore-bearing residue, was followed by cyclization on resin and peptide release to give a mixture of diastereomers.

A new principle for tight junction modulation based on occludin peptides.

The aim of this study was to investigate whether peptides from the extracellular loops of the tight junction protein occludin could be used as a new principle for tight junction modulation. Peptides of 4 to 47 amino acids in length and covering the two extracellular loops of the tight junction protein occludin were synthesized, and their effect on the tight junction permeability in Caco-2 cells was investigated using [14C]mannitol as a para-cellular marker. Lipopeptide derivatives of one of the active occludin peptides (OPs), synthesized by adding a lipoamino acid containing 14 carbon atoms (C14-) to the N terminus of the peptide, were also investigated.

Synthesis of C-terminal glycopeptides from resin-bound glycosyl azides via a modified Staudinger reaction.

The solid-phase synthesis of glycopeptides containing the sugar at the C-terminus is reported. The method is demonstrated on a model, the endogenous antinociceptive peptide Leu-enkephalin. 2,3,4-Tri-O-acetyl-1-azido-1-deoxy-beta-D-glucopyranuronic acid was synthesized and immobilized onto a variety of derivatized resins.

Novel lipoamino acid- and liposaccharide-based system for peptide delivery: application for oral administration of tumor-selective somatostatin analogues.

Lipoamino acid and liposaccharide conjugates of somatostatin analogue TT-232 were synthesized to modify the physicochemical properties of the parent peptide. The relative position, the number, and the nature of the lipid and/or saccharide moieties were varied. Experiments in vitro clearly showed that many compounds modified at the N- and/or C-terminus with lipid or sugar moieties retained the biological activity of the parent compound.