Natural Products for the Prevention and Treatment of Common Cold and Viral Respiratory Infections.

The common cold is generally considered a usually harmless infectious disease of the upper respiratory pathway, with mostly mild symptoms. However, it should not be overlooked, as a severe cold can lead to serious complications, resulting in hospitalization or death in vulnerable patients. The treatment of the common cold remains purely symptomatic.

Pre-Professional International Mobility of European Pharmacy Students-A French Example.

Internationalisation, as well as the need to interact with international partners in academia and in the pharmaceutical industry, brings an international experience to the pharmacist's career, which is essential. The objective of present work is to provide a preliminary study of the current situation of the pre-professional mobility of pharmacy students. It represents the first case study of the international pre-professional mobility of pharmacy students in France, and in north-eastern France in particular.

Molecular Aspects of the Interaction with Gram-Negative and Gram-Positive Bacteria of Hydrothermal Carbon Nanoparticles Associated with Bac8c Antimicrobial Peptide.

Antimicrobial peptides (AMPs) are widely studied as therapeutic agents due to their broad-spectrum efficacy against infections. However, their clinical use is hampered by the low in vivo bioavailability and systemic toxicity. Such limitations might be overcome by using appropriate drug delivery systems.

Plant-Derived Antimicrobial Peptides as Potential Antiviral Agents in Systemic Viral Infections.

Numerous studies have led to a better understanding of the mechanisms of action of viruses in systemic infections for the development of prevention strategies and very promising antiviral therapies. Viruses still remain one of the main causes of human diseases, mainly because the development of new vaccines is usually challenging and drug resistance has become an increasing concern in recent decades. Therefore, the development of potential antiviral agents remains crucial and is an unmet clinical need.

Assessing the correlation of microscopy-based and volumetry-based measurements for resin swelling in a range of potential greener solvents for SPPS.

The degree of resin swelling in a particular solvent system is one of the critical parameters for solid-phase peptide synthesis (SPPS) and for solid-phase synthesis in general. Methods used for measuring the degree of resin swelling include microscopy-based and volumetry-based methods. This study describes and compares the use of both methods for a number of commercially available resins commonly used in SPPS, with a range of solvents, which have been identified in the literature as 'greener' than DCM, DMF and NMP.

Poly(ethylene glycol)-Based Peptidomimetic "PEGtide" of Oligo-Arginine Allows for Efficient siRNA Transfection and Gene Inhibition.

While a wide range of experimental and commercial transfection reagents are currently available, persistent problems remain regarding their suitability for continued development. These include the transfection efficiency for difficult-to-transfect cell types and the risks of decreased cell viability that may arise from any transfection that does occur. Therefore, research is now turning toward alternative molecules that improve the toxicity profile of the gene delivery vector (GDV), while maintaining the transfection efficiency.

Vibrating Mesh Nebulisation of Pro-Antimicrobial Peptides for Use in Cystic Fibrosis.

Background: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung by a vibrating mesh nebuliser (VMN) and whether the pro-AMP modification has any effect on delivery.

Methods: Physical characteristics of the peptides (AMP and pro-AMP) and antimicrobial activity were compared before and after nebulisation.

A novel medical device coating prevents Staphylococcus aureus biofilm formation on medical device surfaces.

Prevention of device related infections due to Staphylococcus aureus biofilms on devices represents a significant challenge. Such infections have recently been shown to be dependent on the coagulation pathway via activation of pro-thrombin and fibrin production. Three direct-thrombin inhibitors, argatroban, hirudin and dabigatran, were examined to determine their effect on preventing S.

Chemoselective Synthesis of N-Terminal Cysteinyl Thioesters via β,γ-C,S Thiol-Michael Addition.

Dehydroalanine (ΔAla) is a highly electrophilic residue that can react efficiently with sulfur nucleophiles to furnish cysteinyl analogues. Herein, we report an efficient synthesis of N-terminal cysteinyl thioesters, suitable for S, N-acyl transfer, based on β,γ-C,S thiol-Michael addition. Both ionic and radical-based methodologies were found to be efficient for this process.

Regeneration of aged DMF for use in solid-phase peptide synthesis.

Dimethylformamide (DMF), which is still the most commonly used solvent for Fmoc-SPPS, has the potential for degradation over time on exposure to air (and water vapour) and storage, to give dimethylamine and formic acid impurities. In particular, dimethylamine can lead to unwanted deprotection of the fluorenylmethyloxycarbonyl (Fmoc) group during, for example, the initial loading of Fmoc amino acids in SPPS, which leads reduced calculated loading values. We have found that treatment of such aged DMF by simple sparging with an inert gas (N ), or vacuum sonication, can regenerate the DMF in order to restore loading levels back to those found for newer, fresh, DMF samples.

Action of antimicrobial peptides and their prodrugs on model and biological membranes.

Antimicrobial peptides (AMPs) are promising broad-spectrum antibiotic candidates in the wake of multi-drug resistant pathogens. Their clinical use still requires a solution based on lead optimisation and/or formulation to overcome certain limitations, such as unwanted cytotoxicity. A prodrug approach could overcome this safety barrier and can be achieved through reversible reduction or neutralisation of the AMPs' net cationic charge.

Biosynthesis of 2-aminooctanoic acid and its use to terminally modify a lactoferricin B peptide derivative for improved antimicrobial activity.

Terminal modification of peptides is frequently used to improve their hydrophobicity. While N-terminal modification with fatty acids (lipidation) has been reported previously, C-terminal lipidation is limited as it requires the use of linkers. Here we report the use of a biocatalyst for the production of an unnatural fatty amino acid, (S)-2-aminooctanoic acid (2-AOA) with enantiomeric excess > 98% ee and the subsequent use of 2-AOA to modify and improve the activity of an antimicrobial peptide.

Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA.

Eradication of Staphylococcus aureus Biofilm Infections Using Synthetic Antimicrobial Peptides.

Here, we demonstrate that antimicrobial peptides (AMPs) are an effective antibiofilm treatment when applied as catheter lock solutions (CLSs) against S. aureus biofilm infections. The activity of synthetic AMPs (Bac8c, HB43, P18, Omiganan, WMR, Ranalexin, and Polyphemusin) was measured against early and mature biofilms produced by methicillin-resistant S.

Using Disease-Associated Enzymes to Activate Antimicrobial Peptide Prodrugs.

Prodrugs of antimicrobial peptides can be generated by modifying their sequences at their N-termini with a linker and a negatively charged promoiety. These modifications can be selectively reversed by a disease-associated enzyme, thereby confining the activity of the peptide to pathologically affected body parts. A general method for the generation of prodrug candidates, based on a linker constituting the substrate of a disease-associated protease and an oligo-glutamic acid promoiety, as well as a protocol to validate the activation of the prodrug, are described herein.

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis.

There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE).

Synthesis and assessment of a maleimide functionalized BF2 azadipyrromethene near-infrared fluorochrome.

The first water soluble maleimide bearing NIR BF2-azadipyrromethene (NIR-AZA) fluorochrome has been synthesised which is capable of rapid thiol conjugations in water with peptides such as glutathione, the cell penetrating peptide (CPP) C(β-A)SKKKKTKV-NH2 and a thiol substituted cRGD. NIR fluorescence imaging showed rapid cellular delivery of the CPP conjugate and effective in vivo tumour localization for the cRGD conjugate.

The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides.

Conjugation of DP18L peptide with (R)-3-hydroxydecanoic acid, derived from the biopolymer polyhydroxyalkanoate, enhances its anti-cancer activity (O'Connor et al., 2013. Biomaterials 34, 2710-2718).

Virtual screening using combinatorial cyclic peptide libraries reveals protein interfaces readily targetable by cyclic peptides.

Protein-protein and protein-peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein-protein and protein-peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein-protein interfaces, built from 3D models available in the Protein Data Bank.

Pro-moieties of antimicrobial peptide prodrugs.

Antimicrobial peptides (AMPs) are a promising class of antimicrobial agents that have been garnering increasing attention as resistance renders many conventional antibiotics ineffective. Extensive research has resulted in a large library of highly-active AMPs. However, several issues serve as an impediment to their clinical development, not least the issue of host toxicity.

Computational approaches to developing short cyclic peptide modulators of protein-protein interactions.

Cyclic peptides are a promising class of bioactive molecules potentially capable of modulating "difficult" targets, such as protein-protein interactions. Cyclic peptides have long been used as therapeutics derived from natural product derivatives, but remain an underexplored class of compounds from the perspective of rational drug design, possibly due to the known weaknesses of peptide drugs in general. While cyclic peptides are non"druglike" by the accepted empirical rules, their unique structure may lend itself to both membrane permeability and proteolytic resistance-the main barriers to oral delivery.

A novel role for the fibrinogen Asn-Gly-Arg (NGR) motif in platelet function.

The integrin αIIbβ3 on resting platelets can bind to immobilised fibrinogen resulting in platelet spreading and activation but requires activation to bind to soluble fibrinogen. αIIbβ3 is known to interact with the general integrin-recognition motif RGD (arginine-glycine-aspartate) as well as the fibrinogen-specific γ-chain dodecapeptide; however, it is not known how fibrinogen binding triggers platelet activation. NGR (asparagine-glycine-arginine) is another integrin-recognition sequence present in fibrinogen and this study aims to determine if it plays a role in the interaction between fibrinogen and αIIbβ3.

Poly(Ethylene glycol)-based backbones with high peptide loading capacities.

Polymer-peptide conjugates are a promising class of compounds, where polymers can be used to overcome some of the limitations associated with peptides intended for therapeutic and/or diagnostic applications. Linear polymers such as poly(ethylene glycol) can be conjugated through terminal moieties and have therefore limited loading capacities. In this research, functionalised linear poly(ethylene glycol)s are utilised for peptide conjugation, to increase their potential loading capacities.