Salivary Antimicrobial Peptide Histatin-5 Does Not Display Zn(II)-Dependent or -Independent Activity against Streptococci.

Histatin-5 (Hst5) is a member of the histatin superfamily of cationic, His-rich, Zn(II)-binding peptides in human saliva. Hst5 displays antimicrobial activity against fungal and bacterial pathogens, often in a Zn(II)-dependent manner. In contrast, here we showed that under conditions that are characteristic of human saliva, Hst5 does not kill seven streptococcal species that normally colonize the human oral cavity and oropharynx.

One-pot ester and thioester formation mediated by pentafluoropyridine (PFP).

Acyl fluorides are valuable synthetic intermediates, but in some cases they can be challenging to handle and difficult to isolate given their susceptibility to degradation. In addition, many reagents utilised to prepare acyl fluorides are incompatible with generation strategies and require the acyl fluoride to be isolated before any further reaction can take place. The combination of these factors has meant that acyl fluorides are currently under investigated in nucleophilic substitution processes, and often only a limited substrate scope is tolerated where they have been used.

Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase.

Non-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity.

Peptoids with Antibiofilm Activity against the Gram Negative Obligate Anaerobe, .

Peptoids (oligo -substituted glycines) are peptide analogues, which can be designed to mimic host antimicrobial peptides, with the advantage that they are resistant to proteolytic degradation. Few studies on the antimicrobial efficacy of peptoids have focused on Gram negative anaerobic microbes associated with clinical infections, which are commonly recalcitrant to antibiotic treatment. We therefore studied the cytotoxicity and antibiofilm activity of a family of peptoids against the Gram negative obligate anaerobe , which is associated with infections in the oral cavity.

Carboxylic Acid Deoxyfluorination and One-Pot Amide Bond Formation Using Pentafluoropyridine (PFP).

This work describes the application of pentafluoropyridine (PFP), a cheap commercially available reagent, in the deoxyfluorination of carboxylic acids to acyl fluorides. The acyl fluorides can be formed from a range of acids under mild conditions. We also demonstrate that PFP can be utilized in a one-pot amide bond formation via generation of acyl fluorides.

Unusually high α-proton acidity of prolyl residues in cyclic peptides.

The acidity of the α-proton in peptides has an essential role in numerous biochemical reactions and underpins their stereochemical integrity, which is critical to their biological function. We report a detailed kinetic and computational study of the acidity of the α-proton in two cyclic peptide systems: diketopiperazine (DKP) and triketopiperazine (TKP). The kinetic acidity (protofugality) of the α-protons were determined though hydrogen deuterium exchange studies in aqueous solutions.

Fengycin A Analogues with Enhanced Chemical Stability and Antifungal Properties.

Fengycins are cyclic lipo-depsipeptides produced by that display potent antifungal properties but are chemically unstable. This instability has meant that no total synthesis of any fengycin has been published. Here we report the synthesis of fengycin A analogues that display enhanced antifungal properties and chemical stability under both basic and acidic conditions.

Quantitative Proteomics Reveals that Hsp90 Inhibition Dynamically Regulates Global Protein Synthesis in Leishmania mexicana.

Heat shock protein 90 (Hsp90) is a conserved molecular chaperone responsible for the folding and maturation of nascent proteins. Hsp90 is regarded as a master regulator of protein homeostasis in the cell, and its inhibition affects the functions of a large array of client proteins. The classical Hsp90 inhibitor tanespimycin has shown potent antileishmanial activity.

F NMR as a tool in chemical biology.

We previously reviewed the use of F NMR in the broad field of chemical biology [Cobb, S. L.; Murphy, C.

Current Synthetic Routes to Peptidyl Mono-Fluoromethyl Ketones (FMKs) and Their Applications.

Peptidyl mono-fluoromethyl ketones (FMKs) are a class of biologically active molecules that show potential as both protease inhibitors for the treatment of a range of diseases and as chemical probes for the interrogation of cellular processes. This review describes the current solid- and solution-phase routes employed for the synthesis of peptidyl mono-FMKs. In addition, it provides a brief overview of some of the key applications of FMKs in the fields of chemical biology and medicinal chemistry.

Synthesis of complex unnatural fluorine-containing amino acids.

The area of fluorinated amino acid synthesis has seen rapid growth over the past decade. As reports of singly fluorinated natural amino acid derivatives have grown, researchers have turned their attention to develop methodology to access complex proteinogenic examples. A variety of reaction conditions have been employed in this area, exploiting new advances in the wider synthetic community such as photocatalysis and palladium cross-coupling.

Unusual Magnetic Field Responsive Circularly Polarized Luminescence Probes with Highly Emissive Chiral Europium(III) Complexes.

Chirality is ubiquitous within biological systems where many of the roles and functions are still undetermined. Given this, there is a clear need to design and develop sensitive chiral optical probes that can function within a biological setting. Here we report the design and synthesis of magnetically responsive Circularly Polarized Luminescence (CPL) complexes displaying exceptional photophysical properties (quantum yield up to 31 % and |g | up to 0.

Recent advances in the development of anti-infective peptoids.

In the search for new sources of antimicrobials many researchers have investigated antimicrobial peptides (AMPs) as templates for the design of innovative therapeutics. However, efforts to develop AMPs in this area has been severely hampered by their inherent susceptibility to enzymatic degradation. Given this only a handful of AMPs are currently in clinical trials.

Protecting Group-Controlled Remote Regioselective Electrophilic Aromatic Halogenation Reactions.

Being able to utilize a protecting group to influence remote regiocontrol offers a simple alternative approach to direct late-stage functionalization of complex organic molecules. However, protecting groups that have the ability to influence reaction regioselectivity remote to their local chemical environment are not widely reported in the literature. Herein, we report the development of remote regioselective electrophilic aromatic substitution (SAr) reactions that are enabled via the application of the tetrafluoropyridyl (TFP) phenol-protecting group.

N-Terminal speciation for native chemical ligation.

Native chemical ligation (NCL) enables the chemical synthesis of peptides via reactions between N-terminal thiolates and C-terminal thioesters under mild, aqueous conditions at pH 7-8. Here we demonstrate quantitatively how thiol speciation at N-terminal cysteines and analogues varies significantly depending upon structure at typical pH values used in NCL.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn-responsive probe (ZRLP) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1.

F NMR Spectroscopy Tagging and Paramagnetic Relaxation Enhancement-Based Conformation Analysis of Intrinsically Disordered Protein Complexes.

The combination of F NMR spectroscopy tagging and paramagnetic relaxation enhancement (PRE) NMR spectroscopy experiments was evaluated as a versatile method to probe protein-protein interactions and conformational changes of intrinsically disordered proteins upon complex formation. The feasibility of the approach is illustrated with an application to the Myc-Max protein complex; this is an oncogenic transcription factor that binds enhancer box DNA fragments. The single cysteine residue of Myc was tagged with highly fluorinated [ F]3,5-bis(trifluoromethyl)benzyl bromide.

An enzymatic Finkelstein reaction: fluorinase catalyses direct halogen exchange.

The fluorinase enzyme from Streptomyces cattleya is shown to catalyse a direct displacement of bromide and iodide by fluoride ion from 5'-bromodeoxyadenosine (5'-BrDA) and 5'-iododeoxyadenosine (5'-IDA) respectively to form 5'-fluorodeoxyadenosine (5'-FDA) in the absence of l-methionine (l-Met) or S-adenosyl-l-methionine (SAM). 5'-BrDA is the most efficient substrate for this enzyme catalysed Finkelstein reaction.

A C-terminal CXCL8 peptide based on chemokine-glycosaminoglycan interactions reduces neutrophil adhesion and migration during inflammation.

Leucocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leucocyte recruitment during the inflammatory response, by signalling through specific chemokine G-protein-coupled receptors (GPCRs). In addition, chemokines interact with cell-surface glycosaminoglycans (GAGs) to generate a chemotactic gradient.

Fluorinated Aromatic Monomers as Building Blocks To Control α-Peptoid Conformation and Structure.

Peptoids are peptidomimetics of interest in the fields of drug development and biomaterials. However, obtaining stable secondary structures is challenging, and designing these requires effective control of the peptoid tertiary amide cis/trans equilibrium. Herein, we report new fluorine-containing aromatic monomers that can control peptoid conformation.

Tetrafluoropyridyl (TFP): a general phenol protecting group readily cleaved under mild conditions.

Phenols are extremely valuable building blocks in the areas of pharmaceuticals, natural products, materials and catalysts. In order to carry out modifications on phenols, the phenolic oxygen is routinely protected to prevent unwanted side reactions. Presently many of the protecting groups available can require harsh conditions, specialist equipment, expensive or air/moisture-sensitive reagents to install and remove.

Short elastin-like peptide-functionalized gold nanoparticles that are temperature responsive under near-physiological conditions.

Thermally-responsive, short elastin-like peptides (ELPs) of sequence VPGVG (V, P and G represent valine, proline and glycine respectively), bearing different N-terminal functional groups (amino-, N-acetyl and thiol) and a non-ionisable C-terminal group, were prepared by solid phase synthesis. The conformation and aggregation properties of the ELPs were studied in different pH aqueous buffer solutions using UV-vis spectroscopy and circular dichroism (CD). The thiol-capped ELPs were used to prepare functionalized gold nanoparticles (GNPs), which were found to undergo thermally-triggered reversible aggregation at 40 °C.

Synthesis of pentafluorosulfanyl (SF) containing aromatic amino acids.

Herein, a series of aromatic pentafluorosulfanyl (SF) containing amino acids are reported. A Negishi cross-coupling strategy utilising a catalyst system of Pd(dba) and SPhos afforded the aforementioned SF amino acids in yields between 32% and 42%. Two dipeptides utilising both the amine and carboxylic functionalities of the synthesised SF containing amino acids were prepared, demonstrating their compatibility with common amide/peptide coupling reagents and strategies.

Amyloid-Beta-Related Angiitis with Distinctive Neuro-Ophthalmologic Features.

Amyloid beta-related angiitis (ABRA) is a subtype of cerebral amyloid angiopathy-related inflammation, with distinctive pathology and prognosis compared with cerebral amyloid angiopathy (CAA). On a spectrum of increasing severity, ABRA is considered to be in-between the less aggressive inflammatory-CAA and the more severe primary central nervous system (CNS) angiitis. Whereas retinal pathological changes were described in subjects with primary or secondary CNS angiitis, and non-inflammatory CAA, bilateral posterior pole superficial and peripapillary retinal hemorrhages have not been reported as initial signs in patients with pathology-confirmed ABRA, accompanying neurological spells and characteristic neuroimaging findings.