BackgroundInfluenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.MethodsWe searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.ResultsThe 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.ConclusionsTo the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.
The aim of this study was to identify the antiviral mechanism of a novel compound, BPR3P0128. From a large-scale screening of a library of small compounds, BPR3P compounds were found to be potent inhibitors of influenza viral replication in MadinDarby canine kidney (MDCK) cells. BPR3P0128 exhibited inhibitory activity against both influenza A and B viruses. The 50% inhibitory concentrations were in the range of 51 to 190 nM in MDCK cells, as measured by inhibition-of-cytopathic-effect assays. BPR3P0128 appeared to target the viral replication cycle but had no effect on viral adsorption. The inhibition of capdependent mRNA transcription by BPR3P0128 was more prominent with a concurrent increase in cap-independent cRNA replication in a primer extension assay, suggesting a role of BPR3P0128 in switching transcription to replication. This reduction in mRNA expression resulted from the BPR3P-mediated inhibition of the cap-dependent endoribonuclease (cap-snatching) activities of nuclear extracts containing the influenza virus polymerase complex. No inhibition of binding of 5= viral RNA to the viral polymerase complex by this compound was detected. BPR3P0128 also effectively inhibited other RNA viruses, such as enterovirus 71 and human rhinovirus, but not DNA viruses, suggesting that BPR3P0128 targets a cellular factor(s) associated with viral PB2 cap-snatching activity. The identification of this factor(s) could help redefine the regulation of viral transcription and replication and thereby provide a potential target for antiviral chemotherapeutics.
Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (T) cell differentiation and T cell metabolism. In vitro, DUSP6 CD4 T cells produced elevated IL-21. In vivo, T cells were increased in DUSP6 mice and in transgenic OTII-DUSP6 mice at steady state. After immunization, DUSP6 and OTII-DUSP6 mice generated more T cells and produced more antigen-specific IgG2 than controls. Activated DUSP6 T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. TCR-stimulated DUSP6 T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6 T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6 T cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains T cell differentiation via inhibiting IL-21 production.
Rainfall during typhoons is one of the most important water resources in Taiwan, but heavy typhoon rainfall often leads to serious disasters and consequently results in loss of lives and property. Hence, accurate forecasts of typhoon rainfall are always required as important information for water resources management and rainfall-induced disaster warning system. In this study, a methodology is proposed for providing quantitative forecasts of 24 h cumulative rainfall during typhoons. Firstly, ensemble forecasts of typhoon rainfall are obtained from an ensemble numerical weather prediction (NWP) system. Then, an evolutionary algorithm, i.e., genetic algorithm (GA), is adopted to real-time decide the weights for optimally combining these ensemble forecasts. That is, the novelty of this proposed methodology is the effective integration of the NWP-based ensemble forecasts through an evolutionary algorithm-based strategy. An actual application is conducted to verify the forecasts resulting from the proposed methodology, namely NWP-based ensemble forecasts with a GA-based integration strategy. The results confirm that the forecasts from the proposed methodology are in good agreement with observations. Besides, the results from the GA-based strategy are more accurate as compared to those by simply averaging all ensemble forecasts. On average, the root mean square error decreases about 7%. In conclusion, more accurate typhoon rainfall forecasts are obtained by the proposed methodology, and they are expected to be useful for disaster warning system and water resources management during typhoons.
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