dChikungunya virus (CHIKV; genus Alphavirus) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast, there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome. Active forms of replicase enzymes are generated using the autoproteolytic activity of nsP2. The available three-dimensional (3D) structure of nsP2 protease has made it a target for in silico drug design; however, there is thus far little evidence that the designed compounds indeed inhibit the protease activity of nsP2 and/or suppress CHIKV replication. In this study, a set of 12 compounds, predicted to interact with the active center of nsP2 protease, was designed using target-based modeling. The majority of these compounds were shown to inhibit the ability of nsP2 to process recombinant protein and synthetic peptide substrates. Furthermore, all compounds found to be active in these cell-free assays also suppressed CHIKV replication in cell culture, the 50% effective concentration (EC 50 ) of the most potent inhibitor being ϳ1.5 M. Analysis of stereoisomers of one compound revealed that inhibition of both the nsP2 protease activity and CHIKV replication depended on the conformation of the inhibitor. Combining the data obtained from different assays also indicates that some of the analyzed compounds may suppress CHIKV replication using more than one mechanism. C hikungunya virus (CHIKV; genus Alphavirus, family Togaviridae) is the causative agent of chikungunya fever, a disease that has affected millions in the last decade. It is characterized by high fever, arthralgia, myalgia, headache, and rash. The disease is usually self-limiting; however long-lasting chronic symptoms are observed in nearly 50% of CHIKV-infected patients (1). As there is no approved vaccine or specific licensed antiviral compounds (2), the treatment of CHIKV infection is largely based on relief of symptoms.CHIKV infection can be inhibited by targeting host factors essential for virus infection. Targeting of several metabolic pathways has revealed anti-CHIKV effects of several licensed drugs (3). Compounds most likely targeting virus entry or host cell-specific components required for virus infection have been described (4-8). Several nucleosides or nucleotides, acting as pseudosubstrates for CHIKV RNA-dependent RNA polymerase and/or using another, more general mechanism of action, have shown anti-CHIKV activity (9). In addition, anti-CHIKV effects have been described for several groups of novel synthetic compounds (10-12).Computer-aided design based on molecular docking and molecular dynamics simulations and pharmacophore approach allows identifying potential in silico hits as active inhibitors for different CHIKV replicase proteins. This approach, however, requires the three-dimensional (3D) structure...

Neuropathic pain is a chronic pain condition caused by lesion or disease affecting the somatosensory system. The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of NP and stimulate regeneration of sensory neurons in vivo. Here we report the development of the compound BT18 that selectively activates GFL receptors, alleviates pain and restores damaged dorsal root ganglion (DRG) neurons in rat models of NP. Significance statementNeuropathic pain (NP) is a chronic syndrome caused by different diseases and lesions affecting nervous system. Earlier studies demonstrated that neurotrophic factors -the glial cell line-derived neurotrophic factor (GDNF) and artemin -could reverse the damage done by lesions in animal models of NP. We demonstrate for the first time that a small molecule can activate receptor of GDNF and artemin, it alleviates pain symptoms in vivo in two animal models of NP and restores to normal the molecular markers expressed in sensory neurons. This compound, termed BT18, can pave way for creating novel disease modifying therapies for NP.

Quick characterization methods to determine the structure of carbon materials are sought after for a wide array of technical applications. In this study we present the combined analysis of the structure of carbide-derived carbons (CDCs) with Raman spectroscopy and wide-angle X-ray scattering (WAXS) methods. We present the optimal deconvolution method to be used for the detailed analysis of Raman spectroscopy data of CDCs and comparison to corresponding WAXS results is made. For a broad set of CDCs both WAXS and Raman spectroscopy data showed that the average graphene layer extent increases with synthesis temperature of CDC, while the coherent domain lengths obtained from Raman spectroscopy higher by an average of 4.4 nm. In addition, the presence of correlations between the parameters (D-band width and the parameter A∑D/A∑G) from Raman spectroscopy and the synthesis temperature are established. Based on the WAXS and Raman spectra data analysis the strong influence of the precursor carbide structure on the graphitization pathway is shown.