ZIKV Inhibitors Based on Pyrazolo[3,4-d]pyridazine-7-one Core: Rational Design, In Vitro Evaluation, and Theoretical Studies.

The Zika virus (ZIKV) is believed to cause birth defects, and no anti-ZIKV drugs have been approved by medical organizations to date. Starting from antimicrobial lead compounds with a pyrazolo[3,4-d]pyridazine-7-one scaffold, we synthesized 16 derivatives and screened their ability to interfere with ZIKV infection utilizing a cell-based phenotypic assay. Of these, five compounds showed significant inhibition of ZIKV with a selective index value greater than 4.6. In particular, compound 9b showed the best anti-ZIKV activity with a selectivity index of 22.4 (half-maximal effective concentration = 25.6 µM and 50% cytotoxic concentration = 572.4 µM). Through the brine shrimp lethality bioassay, 9b, 10b, 12, 17a, and 19a showed median lethal dose values in a range of 87.2-100.3 µg/mL. Compound 9b was also targeted to the NS2B-NS3 protease of ZIKV using molecular docking protocols, in which it acted as a noncompetitive inhibitor and strongly bound to five key amino acids (His51, Asp75, Ser135, Ala132, Tyr161). Utilizing the pharmacophore model of 9b, the top 20 hits were identified as prospective inhibitors of NS2B-NS3 protease, and six of them were confirmed for their stability with the protease via redocking and molecular dynamics simulations.

Screening analysis of organic micro-pollutants in road dusts from some areas in northern Vietnam: A preliminary investigation on contamination status, potential sources, human exposure, and ecological risk.

Road dust samples collected from some representative areas in northern Vietnam were examined to determine the occurrence of multiple classes of organic micro-pollutants. Of 942 target compounds screened, 105 organic pollutants originating from different sources such as traffic, household, agricultural, and industrial activities, were detected at least once in our samples. Concentrations of total organic pollutants in the road dusts ranged from 7.8 to 170 µg g-1, with a median value of 28 µg g-1. Overall contamination levels were the highest in samples from an urban area, followed by those from an industrial park, a suburban area, and a rural commune, suggesting environmental impacts of urbanization and industrialization. The most predominant pollutants found in the road dusts were n-alkanes, polycyclic aromatic hydrocarbons (PAHs), and current-use chemicals such as phthalate plasticizers and pharmaceutical and personal care products (PPCPs), whereas, industrial chemicals and pesticides were detected at relatively low levels. Persons occupationally exposed to road dusts (e.g., street sweepers, vendors, and traffic policemen) were estimated to receive the highest daily intake doses of dust-bound organic pollutants that were one to two orders of magnitude greater than those received by general population. No serious human health risk associated with ingestion of contaminated road dusts was observed in this study. However, levels of some phthalates were higher than related environmental quality guidelines in terms of ecological risk. More comprehensive and detailed risk assessment of organic pollutants in road dusts should be conducted, especially for highly urbanized and industrialized areas in developing countries.

Development of a monoclonal antibody specific to envelope domain III with broad-spectrum detection of all four dengue virus serotypes.

Dengue virus (DENV) is a mosquito-borne pathogen that annually infects more than 390 million people in 100 different countries. Symptoms of the viral infection include a relatively weak dengue fever to severe dengue hemorrhagic fever/dengue shock syndrome, which are mortal infectious diseases. As of yet, there is no commercially available vaccine or therapeutic for DENV. Currently, passive immunotherapy using DENV-specific antibody (Ab) is a considered strategy to treat DENV infection. Here, we developed a monoclonal Ab (mAb), EDIIImAb-61, specific to the DENV domain III of the envelope glycoprotein (EDIII) with broad-spectrum detection ability to all four DENV serotypes (DENV-1∼4) to use as a therapeutic Ab. Although EDIII contains non-immunodominant epitopes compared to domains I and II, domain III plays a critical role in host receptor binding. EDIIImAb-61 exhibited cross-reactive binding affinity to all four DENV serotypes that had been isolated from infected humans. To further characterize EDIIImAb-61 and prepare genes for large-scale production using a heterologous expression system, the sequence of the complementarity determining regions was analyzed after cloning the full-length cDNA genes encoding the heavy and light chain of the mAb. Finally, we produced Ab from CHO-K1 cells transfected with the cloned EDIIImAb-61 heavy and light chain genes and confirmed the binding ability of the Ab. Collectively, we conclude that EDIIImAb-61 itself and the recombinant Ab produced using the cloned heavy and light chain gene of EDIIImAb-61 is a candidate for passive immunotherapy against DENV infection.