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A high-throughput screen of preclinical, investigational and FDA-approved drugs identifies compounds that possess antiviral and neuroprotective effects against Zika virus infection in human neural progenitor cells and astrocytes. In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

The Fuxian-Yan10 layers are the main oil-producing reservoirs of Jurassic in Wuqi–Dingbian area of Ordos Basin. However, due to the lack of understanding of the pattern and distribution characteristics of oil reservoirs, the benefits of exploration and development are restricted. In order to provide theoretical guidance for the study of similar geological features, based on the analysis of paleogeomorphic features and evolution, the analysis focuses on the influence of palaeo-geomorphology on oil reservoir distribution, and summarizes the main types of reservoir models in the study area. The results show that there are four types of palaeo-geomorphic units in the Wuding area: palaeo-river, slope, highland and interriver hill. In the study area, the Jurassic paleogeomorphology controls the sedimentary development and distribution from Fuxian Formation to Yan 9 Formation. The compacted structure and lithologic barrier provide good trapping conditions for the paleogeomorphic oil. Moreover, the swampy coal measures and mudstone at the top of Yan 9 play a sealing role for oil accumulation, and the bottom water was obviously driven. In addition, the pre-Jurassic deep valley was the main channels for oil migration. On this basis, it is concluded that there are four reservoir-forming models in Wuding area: slope type, river hill type, ancient river type and highland type.

Recent outbreaks of Zika virus （ZIKV） highlight an urgent need for therapeutics. The protease complex NS2B- NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B- NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

Chemical genomics aims to comprehensively define, and ultimately predict, the effects of small molecule compounds on biological systems. Chemical activity profiling approaches must consider chemical effects on all pathways operative in mammalian cells. To enable a strategic and maximally efficient chemical profiling of pathway space, we have created the NCATS BioPlanet, a comprehensive integrated pathway resource that incorporates the universe of 1,658 human pathways sourced from publicly available, manually curated sources, which have been subjected to thorough redundancy and consistency cross-evaluation. BioPlanet supports interactive browsing, retrieval, and analysis of pathways, exploration of pathway connections, and pathway search by gene targets, category, and availability of corresponding bioactivity assay, as well as visualization of pathways on a 3-dimensional globe, in which the distance between any two pathways is proportional to their degree of gene component overlap. Using this resource, we propose a strategy to identify a minimal set of 362 biological assays that can interrogate the universe of human pathways. The NCATS BioPlanet is a public resource, which will be continually expanded and updated, for systems biology, toxicology, and chemical genomics, available at http://tripod.nih.gov/bioplanet/.

Target-specific, mechanism-oriented in vitro assays post a promising alternative to traditional animal toxicology studies. Here we report the first comprehensive analysis of the Tox21 effort, a large-scale in vitro toxicity screening of chemicals. We test ∼10,000 chemicals in triplicates at 15 concentrations against a panel of nuclear receptor and stress response pathway assays, producing more than 50 million data points. Compound clustering by structure similarity and activity profile similarity across the assays reveals structure–activity relationships that are useful for the generation of mechanistic hypotheses. We apply structural information and activity data to build predictive models for 72 in vivo toxicity end points using a cluster-based approach. Models based on in vitro assay data perform better in predicting human toxicity end points than animal toxicity, while a combination of structural and activity data results in better models than using structure or activity data alone. Our results suggest that in vitro activity profiles can be applied as signatures of compound mechanism of toxicity and used in prioritization for more in-depth toxicological testing. Large-scale in vitro assays may reduce the number of toxicological tests carried out in animals. Here, Huang et al . report a large dataset containing results of in vitro tests of approximately 10,000 chemicals, and use these data to create models that can potentially predict toxicity in humans.

ICRF193 is a catalytic inhibitor of Topoisomerase 2 (TOP2), one of the major targets in cancer therapy. Although ICRF193 has not been approved for clinical use, it has potential implications in chemotherapy. In this study, we aimed to investigate the use of ICRF193 in chemotherapy in co-treatment with other drugs. To identify compounds that have synergistic effects with ICRF193, we optimized a cytotoxicity assay with combinations of ICRF193 in a 1536-well plate format and screened 2678 compounds, including clinically approved and investigational drugs, for their cytotoxicity in the presence and absence of ICRF193. From the screening and confirmation assays, etoposide, a known TOP2-targeting drug, was found to have a synergistic effect with 200 nM ICRF193 across multiple cancer cell lines, including HCT116, MCF7, and T47D. On the other hand, ICRF193 suppressed the toxicity of etoposide at higher concentrations (> 10 µM). In the follow-up studies, we found that ICRF193 and etoposide synergistically induced DNA double-strand breaks and subsequent G2 phase accumulation. Interestingly, this synergistic effect was observed only with etoposide and not with other TOP2 inhibitors in the tested compound library. Taken together, our results indicate that ICRF193 has a specific functional interaction with etoposide that enhances its genotoxic potential.

Natural Products (NPs) are increasingly utilized worldwide for their potential therapeutic benefits, including central nervous system (CNS) disorders. Studies have shown açai berries mitigating Parkinson’s disease progression through dopaminergic neuroprotection via Nrf-2 HO-1 pathways. Ashwagandha, an evergreen shrub, has shown potential as a therapeutic for neurodegenerative disorders via axonal regeneration in Aβ25-35-treated cortical neurons in vitro. In most cases, promising NPs are tested using in vitro assays or simpler systems during the early stages of drug discovery. However, a critical challenge lies in the lack of data on blood-brain barrier (BBB) penetration, which is a significant determinant for the successful development of CNS drugs. Our first goal was to test our in-house NP constituent library via the Parallel Artificial Membrane Permeability Assay (PAMPA-BBB), with the aim of understanding their BBB-penetration potential. Of the constituents tested, 255 were found to have moderate to high BBB permeability. Our next goal was to understand if these compounds could exhibit CNS toxicity. Neuronal viability and neurite outgrowth assays were performed with this subset to identify compounds with neurotoxicity potential. Around 35% of compounds tested showed neurite outgrowth inhibition. The habitual and widespread consumption of NPs underscores the importance of subjecting this subset of compounds to additional testing and validation in vivo to ascertain their potential detrimental effects. Understanding BBB permeability and assessing neurotoxicity mechanisms of NPs will significantly benefit the CNS drug discovery community.

Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Quantitative structure-activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro-in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634-641; http://dx.doi.org/10.1289/ehp.1509763.

Background/aims The expression levels of long non-coding RNA XIST are significantly associated with paclitaxel (Pac) sensitivity in ovarian cancer, but the mechanism of action remains unclear. Therefore, this experimental design was based on lncRNA XIST analysis to regulate the effect of XIST on the tumor stem cell and paclitaxel sensitivity in ovarian cancer. Methods Sphere assay and fluorescence activated cell sorting (FACS) were used to determine the expression levels of XIST and sensitivity to paclitaxel treatment. The effect of the proliferation was detected by MTT assay. Target gene prediction and screening, luciferase reporter assays were used to validate downstream target genes for lncRNA XIS and KMT2C. The expression of KMT2C was detected by RT-qPCR and Western blotting. RT-qPCR was used to detect the expression of cancer stem cell-associated genes SOX2, OCT4 and Nanog. The tumor changes in mice were detected by in vivo experiments in nude mice. Results There was an inverse correlation between the expression of XIST and cancer stem cell (CD44 + /CD24−) population. XIST promoted methylation of histone H3 methylation at lysine 4 by enhancing the stability of lysine (K)-specific methyltransferase 2C (KMT2C) mRNA. XIST acted on the stability of KMT2C mRNA by directly targeting miR-93-5p. Overexpression of miR-93-5p can reverse the XIST overexpression-induced KMT2C decrease and sphere number increase. Overexpression of KMT2C inhibited XIST silencing-induced proliferation of cancer stem cells, and KMT2C was able to mediate paclitaxel resistance induced by XIST in ovarian cancer. The study found that XIST can affect the expression of KMT2C in the ovarian cancer via targeting miR-93-5p. Conclusion XIST promoted the sensitivity of ovarian cancer stem cells to paclitaxel in a KMT2C-dependent manner.

Currently, various potential therapeutic agents for coronavirus disease-2019 (COVID-19), a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are being investigated worldwide mainly through the drug repurposing approach. Several anti-viral, anti-bacterial, anti-malarial, and anti-inflammatory drugs were employed in randomized trials and observational studies for developing new therapeutics for COVID-19. Although an increasing number of repurposed drugs have shown anti-SARS-CoV-2 activities in vitro , so far only remdesivir has been approved by the US FDA to treat COVID-19, and several other drugs approved for Emergency Use Authorization, including sotrovimab, tocilizumab, baricitinib, paxlovid, molnupiravir, and other potential strategies to develop safe and effective therapeutics for SARS-CoV-2 infection are still underway. Many drugs employed as anti-viral may exert unwanted side effects (i.e., toxicity) via unknown mechanisms. To quickly assess these drugs for their potential toxicological effects and mechanisms, we used the Tox21 in vitro assay datasets generated from screening ∼10,000 compounds consisting of approved drugs and environmental chemicals against multiple cellular targets and pathways. Here we summarize the toxicological profiles of small molecule drugs that are currently under clinical trials for the treatment of COVID-19 based on their in vitro activities against various targets and cellular signaling pathways.