Surface engineering of metal-organic framework nanoparticles-based miRNA carrier: Boosting RNA stability, intracellular delivery and synergistic therapy.

MicroRNAs (miRNAs) are small noncoding RNAs that are critical for the regulation of multiple physiological and pathological processes, thus holding great clinical potential. However, the therapeutic applications of miRNAs are severely limited by their biological instability and poor intracellular delivery. Herein, we describe a dual-layers surface engineering strategy to design an efficient miRNA delivery nanosystem based on metal-organic frameworks (MOFs) incorporating lipid coating.

Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol.

This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new pharmaceutical for treatment of antibiotic-resistant biofilm infections. The potentially hazardous diazotisation step in the lab-scale synthesis was transformed to a safe and easy-to-handle flow chemistry step. Additionally, the paper presents an OSHA-recommended safety assessment of active compound , as performed by Fauske and Associates, LLC, Burr Ridge, IL, USA.

Chemoenzymatic indican for light-driven denim dyeing.

Blue denim, a billion-dollar industry, is currently dyed with indigo in an unsustainable process requiring harsh reducing and alkaline chemicals. Forming indigo directly in the yarn through indican (indoxyl-β-glucoside) is a promising alternative route with mild conditions. Indican eliminates the requirement for reducing agent while still ending as indigo, the only known molecule yielding the unique hue of blue denim.

Inhibition of quorum sensing by chemical induction of the MexEF-oprN efflux pump.

The cell-to-cell communication system quorum sensing (QS), used by various pathogenic bacteria to synchronize gene expression and increase host invasion potentials, is studied as a potential target for persistent infection control. To search for novel molecules targeting the QS system in the Gram-negative opportunistic pathogen , a chemical library consisting of 3,280 small compounds from LifeArc was screened. A series of 10 conjugated phenones that have not previously been reported to target bacteria were identified as inhibitors of QS in .

Chemokine N-terminal-derived peptides differentially regulate signaling by the receptors CCR1 and CCR5.

Inflammatory chemokines are often elevated in disease settings, where the largest group of CC-chemokines are the macrophage inflammatory proteins (MIP), which are promiscuous for the receptors CCR1 and CCR5. MIP chemokines, such as CCL3 and CCL5 are processed at the N terminus, which influences signaling in a highly diverse manner. Here, we investigate the signaling capacity of peptides corresponding to truncated N termini.

Re-routing GPR56 signalling using Gα G protein chimeras.

Adhesion G protein-coupled receptors (aGPCRs) constitute the second largest subclass of the GPCR superfamily. Although canonical GPCRs are explored pharmacologically as drug targets, no clinically approved drugs target the aGPCR family so far. The aGPCR GPR56/ADGRG1 stands out as an especially promising target, given its direct link to the monogenetic disease bilateral frontoparietal polymicrogyria and implications in cancers.

Convergent Total Synthesis of Exochelin 772SM.

A convergent total synthesis of the natural mycobacterial iron chelator desferri-exochelin 772SM (D-EXO) is described. The synthetic procedure proceeds in 11 steps in the longest linear sequence, with an overall yield of 8.6%.

A genetic switch controls Pseudomonas aeruginosa surface colonization.

Efficient colonization of mucosal surfaces is essential for opportunistic pathogens like Pseudomonas aeruginosa, but how bacteria collectively and individually adapt to optimize adherence, virulence and dispersal is largely unclear. Here we identified a stochastic genetic switch, hecR-hecE, which is expressed bimodally and generates functionally distinct bacterial subpopulations to balance P. aeruginosa growth and dispersal on surfaces.

Targeted delivery of alcohol-containing payloads with antibody-drug conjugates.

We herein describe the cell-specific release of alcohol-containing payloads a sulfatase-sensitive linker in antibody-drug conjugates (ADCs). The linker shows efficient sulfatase-mediated release and high stability in human and mouse plasma. evaluation demonstrates potent antigen dependent toxicity towards breast cancer cell lines.

Structural design of anthraquinone bridges in direct electron transfer of fructose dehydrogenase.

Multi-functional small molecules attached to an electrode surface can bind non-covalently to the redox enzyme fructose dehydrogenase (FDH) to ensure efficient electrochemical electron transfer (ET) and electrocatalysis of the enzyme in both mediated (MET) and direct (DET) ET modes. The present work investigates the potential of exploiting secondary, electrostatic and hydrophobic interactions between substituents on a small molecular bridge and the local FDH surfaces. Such interactions ensure alignment of the enzyme in an orientation favourable for both MET and DET.

Solid-phase synthesis and biological evaluation of piperazine-based novel bacterial topoisomerase inhibitors.

There is an emerging global need for new and more effective antibiotics against multi-resistant bacteria. This situation has led to massive industrial investigations on novel bacterial topoisomerase inhibitors (NBTIs) that target the vital bacterial enzymes DNA gyrase and topoisomerase IV. However, several of the NBTI compound classes have been associated with inhibition of the hERG potassium channel, an undesired cause of cardiac arrhythmia, which challenges medicinal chemistry efforts through lengthy synthetic routes.

SAR study of 4-arylazo-3,5-diamino-1-pyrazoles: identification of small molecules that induce dispersal of biofilms.

By screening of a collection of 50 000 small-molecule compounds, we recently identified 4-arylazo-3,5-diamino-1-pyrazoles as a novel group of anti-biofilm agents. Here, we report a SAR study based on 60 analogues by examining ways in which the pharmacophore can be further optimized, for example, substitutions in the aryl ring. The SAR study revealed the very potent anti-biofilm compound 4-(2-(2-fluorophenyl)hydrazineylidene)-5-imino-4,5-dihydro-1-pyrazol-3-amine ().

Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms.

Microbial biofilms are involved in a number of infections that cannot be cured, as microbes in biofilms resist host immune defenses and antibiotic therapies. With no strict biofilm-antibiotic in the current pipelines, there is an unmet need for drug candidates that enable the current antibiotics to eradicate bacteria in biofilms. We used high-throughput screening to identify chemical compounds that reduce the intracellular c-di-GMP content in Pseudomonas aeruginosa.

Production of allergen-specific immunotherapeutic agents for the treatment of food allergy.

Allergen-specific immunotherapy (IT) is emerging as a viable avenue for the treatment of food allergies. Clinical trials currently investigate raw or slightly processed foods as therapeutic agents, as trials using food-grade agents can be performed without the strict regulations to which conventional drugs are subjected. However, this limits the ability of standardization and may affect clinical trial outcomes and reproducibility.

Small Molecule Anti-biofilm Agents Developed on the Basis of Mechanistic Understanding of Biofilm Formation.

Microbial biofilms are the cause of persistent infections associated with various medical implants and distinct body sites such as the urinary tract, lungs, and wounds. Compared with their free living counterparts, bacteria in biofilms display a highly increased resistance to immune system activities and antibiotic treatment. Therefore, biofilm infections are difficult or impossible to treat with our current armory of antibiotics.

Correction: Gold-carbonyl group interactions in the electrochemistry of anthraquinone thiols self-assembled on Au(111)-surfaces.

[This corrects the article DOI: 10.1039/C9SC00061E.].

Gold-carbonyl group interactions in the electrochemistry of anthraquinone thiols self-assembled on Au(111)-surfaces.

New anthraquinone derivatives with either a single or two thiol groups (AQ1 and AQ2) were synthesized and immobilized in self-assembled monolayers (SAMs) on Au(111) electrodes Au-S bonds. The resultant AQ1- and AQ2-SAMs were studied by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), which enabled mapping of the gold-carbonyl group interactions and other dynamics in the Au-S bound molecular framework. Understanding of these interactions is important for research on thiol-coated gold nanoclusters, since (I) anthraquinone derivatives are a major compound family for providing desired redox functionality in multifarious assays or devices, and (II) the gold-carbonyl interactions can strongly affect anthraquinone electrochemistry.

Itaconimides as Novel Quorum Sensing Inhibitors of .

is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity.

Bead-based screening in chemical biology and drug discovery.

High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amenable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structurally diverse libraries for early drug discovery.

Photolabile Linkers for Solid-Phase Synthesis.

Photolabile linkers are the subjects of intense research because they allow the release of the target molecule simply by irradiation. Photochemical release of synthesis products is often facilitated without additional reagents under mild reaction conditions, which may even be environmentally friendly and appealing in the context of greener chemistry. The mild conditions also allow for applications of released material in subsequent biological screening experiments, where contamination with cleavage reagents would be detrimental.

Oxidative Modification of Tryptophan-Containing Peptides.

We herein present a broadly useful method for the chemoselective modification of a wide range of tryptophan-containing peptides. Exposing a tryptophan-containing peptide to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in a selective cyclodehydration between the peptide backbone and the indole side chain of tryptophan to form a fully conjugated indolyl-oxazole moiety. The modified peptides show a characteristic and significant emission maximum at 425 nm, thus making the method a useful strategy for fluorescence labeling.

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors.

We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids.

Solvent-Controlled Chemoselectivity in the Photolytic Release of Hydroxamic Acids and Carboxamides from Solid Support.

The synthetic utility and theoretical basis of a photolabile hydroxylamine-linker are presented. The developed protocols enable the efficient synthesis and chemoselective photolytic release of either hydroxamates or carboxamides from solid support. The bidetachable mode of the linker unit is uniquely dependent on the solvent.

Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists.

Peroxisome proliferator-activated receptor γ (PPARγ) is a well-known target for thiazolidinedione antidiabetic drugs. In this paper, we present the synthesis and biological evaluation of a series of dihydropyrano[2,3-c]pyrazole derivatives as a novel family of PPARγ partial agonists. Two analogues were found to display high affinity for PPARγ with potencies in the micro molar range.