The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA's role as a biomarker, for ...example, to distinguish between various sub-forms or stages of a given disease of interest, research is also ongoing to utilize these small nucleic acids as therapeutics. An example of a common pleiotropic disease that could benefit from miRNA-based therapeutics is inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the small and large intestines. Due to complex interactions between multiple factors in the etiology of IBD, development of therapies that effectively maintain remission for this disease is a significant challenge. In this review, we discuss the role of dysregulated miRNA expression in the context of clinical ulcerative colitis (UC) and Crohn's disease (CD)-the two main forms of IBD-and the various preclinical mouse models of IBD utilized to validate the therapeutic potential of targeting these miRNA. Additionally, we highlight advances in the development of genetically engineered animal models that recapitulate clinical miRNA expression and provide powerful preclinical models to assess the diagnostic and therapeutic promise of miRNA in IBD.
Self-assembly of components larger than molecules into ordered arrays is an efficient way of preparing microstructured materials with interesting mechanical and optical properties. Although ...crystallization of identical particles or particles of different sizes or shapes can be readily achieved, the repertoire of methods to assemble binary lattices of particles of the same sizes but with different properties is very limited. This paper describes electrostatic self-assembly of two types of macroscopic components of identical dimensions using interactions that are generated by contact electrification. The systems we have examined comprise two kinds of objects (usually spheres) made of different polymeric materials that charge with opposite electrical polarities when agitated on flat, metallic surfaces. The interplay of repulsive interactions between like-charged objects and attractive interactions between unlike-charged ones results in the self-assembly of these objects into highly ordered, closed arrays. Remarkably, some of the assemblies that form are not electroneutral-that is, they possess a net charge. We suggest that the stability of these unusual structures can be explained by accounting for the interactions between electric dipoles that the particles in the aggregates induce in their neighbours.
The quinolone class of antibacterial agents has a proven track record over the past several decades for the treatment of bacterial infections. Their unique mechanism of action and bactericidal ...properties make them attractive therapeutic agents.
Significant research efforts continue to the present day in both academia and industry, which have provided a number of promising drug candidates for further development. This review examines quinolones that have been approved for market, entered into clinical trials or reported in the literature during 2005 - 2010.
The reader will be provided with background information on the quinolones as well as recent research findings that demonstrate the continued utility of the class as antibacterial agents. The review highlights a number of recently reported compounds of interest.
Despite nearly 40 years of research, quinolones still provide new analogs of both scientific and clinical interest. Compounds that are active against antibiotic resistant strains including multiple drug-resistant Mycobacterium tuberculosis as well as compounds with improved pharmacokinetic and safety profiles are goals for current and future programs in this area.
Odalasvir is a selective inhibitor of hepatitis C virus NS5A protein, a key target for combination therapies. This paper describes the chemical process development for the synthesis of this active ...pharmaceutical ingredient and the improvements that were achieved over the medicinal chemistry route. Optimization of all of the reaction conditions and crystallizations resulted in higher throughput and a highly improved process mass intensity. The process is robust and has been scaled up to ∼100 kg batches without issues.
Pseudoxanthoma elasticum, a prototype of heritable multisystem ectopic mineralization disorders, is caused by mutations in the ABCC6 gene encoding a putative efflux transporter, ABCC6. The phenotypic ...spectrum of pseudoxanthoma elasticum varies, and the correlation between genotype and phenotype has not been established. To identify genetic modifiers, we performed quantitative trait locus analysis in inbred mouse strains that carry the same hypomorphic allele in Abcc6 yet with highly variable ectopic mineralization phenotypes of pseudoxanthoma elasticum. Abcc6 was confirmed as a major determinant for ectopic mineralization in multiple tissues. Integrative analysis using functional genomics tools that included GeneWeaver, String, and Mouse Genome Informatics identified a total of nine additional candidate modifier genes that could influence the organ-specific ectopic mineralization phenotypes. Integration of the candidate genes into the existing ectopic mineralization gene network expands the current knowledge on the complexity of the network that, as a whole, governs ectopic mineralization in soft connective tissues.
Display omitted
•Exploited a metallocene to gain access to a biplanar pharmacophoric arrangement.•Leveraged this organometallic architecture in the design of potent anti-HCV agents.•These efforts ...informed the design of the clinical candidate odalasvir (ACH-3102).
An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1′-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.
Complement alternative pathway (AP) dysregulation has been implicated in geographic atrophy, an advanced form of age-related macular degeneration. Danicopan is an investigational, first-in-class ...inhibitor of factor D, an essential AP activation enzyme. We assessed danicopan distribution to the posterior segment of the eye after oral dosing.
Tissue distribution of drug-derived radioactivity was evaluated using whole-body autoradiography following oral administration of 14C-danicopan to pigmented and albino rats. Pharmacokinetics and ocular tissue distribution were studied in pigmented and albino rabbits following single and multiple oral dosing of danicopan. The melanin binding property was characterized in vitro.
Radioactivity was distributed widely in rats and became nonquantifiable in most tissues 24 hours postdose except in the pigmented rat uvea (quantifiable 672 hours postdose). Danicopan binding to melanin was established in vitro. After single dosing, the maximum concentration (Cmax) and area under the curve (AUC) in neural retina and plasma were similar in both rabbit types. After multiple dosing, AUC in neural retina was 3.4-fold higher versus plasma in pigmented rabbits. Drug levels in choroid/Bruch's membrane (BrM)/retinal pigment epithelium (RPE) were similar to plasma in albino rabbits but higher in pigmented rabbits: Cmax and AUC were 2.9- and 23.8-fold higher versus plasma after single dosing and 5.8- and 62.7-fold higher after multiple dosing. In pigmented rabbits, ocular tissue exposures slowly declined over time but remained quantifiable 240 hours postdose.
The results demonstrate that danicopan crosses the blood-retina barrier and binds melanin reversibly, leading to a higher and more sustained exposure in melanin-containing ocular tissues (choroid/BrM/RPE) and in the neural retina as compared to in plasma after repeated oral dosing in pigmented animals.
These findings suggest that oral danicopan possesses potential for treating geographic atrophy because AP dysregulation in the posterior segment of the eye is reported to be involved in the disease pathogenesis.
We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and ...related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.
This report is a study of the kinetics of contact charging resulting from the rolling of millimeter-sized metallic spheres on flat surfaces of polystyrene (PS). Charging was studied (i) for different ...values of the relative humidity (RH) of the air in contact with the system, (ii) in acidic and basic atmospheres, and (iii) for a series of PS surfaces oxidized to different degrees. The rates of charging increased with increasing RH; they were higher in basic atmospheres than in neutral or acidic ones and correlated with the numbers of hydrophilic groups on the surface of the polymer. These findings are consistent with a mechanism that implicates a thin film of water on the surface of PS as an important element of tribocharging in this system.
We describe an analytical system for in situ measurement of the charge that develops by contact electrification when a ferromagnetic sphere rolls on the surface of a polymer. This system makes it ...possible to survey the ability of polymeric surfaces to charge by contact electrification. Because the measurement of charge using this tool does not require physical contact of the charged sphere with the measuring electrode, it also enables the kinetics of charging to be examined. The research has focused on the contact charging of spheres having a core-and-shell geometry (a common core of ferromagnetic steel, and a variable shell of thin films of metals, or metals with surface oxides) rolling on the surface of polymeric slabs; it has generated an internally consistent set of data that include the polarity and magnitude of charging for a homologous series of polymers that differ chemically in the pendant group on a polyethylene backbone.
PDF
