Discovery of a small-molecule inhibitor targeting the ovarian tumor domain of a novel Tamdy orthonairoviruse associated with human febrile illness.

Tick-borne orthonairoviruses have been characterized as a global health threat to humans and animals. Tacheng Tick virus 1 (TcTV-1) from this family was provided as evidence that is associated with the febrile illness syndrome. Here, we first identify and demonstrate that the ovarian tumor (OTU) domain of TcTV-1 has remarkable deubiquitinating activity both in vitro and in vivo. By solving the crystal structure of TcTV-1 OTU (tcOTU) domain and comparing it to that of human deubiquitinating enzymes, we found that overall structures of tcOTU and human OTU family are similar, but the residues involved in the catalytic pocket vary widely. Based on the tcOTU domain we screened 5090 bioactive compounds and found mecobalamin had a good effect on suppressing the deubiquitinating activity. The structural model of tcOTU and mecobalamin suggests that mecobalamin occupies the site of the substrate Ub, by blocking the substrate binding to the enzyme. Thus, our results showed OTU domain of TcTV-1 has a robust deubiquitinating activity and mecobalamin or its derivatives might be promising candidates for the treatment or prevention of disease caused by the TcTV-1 virus.

Investigation of the microRNAs in safflower seed, leaf, and petal by high-throughput sequencing.

Safflower (Carthamus tinctorius L.) is one of the most important crop plants that has been utilized for production of oleosins. miRNAs (microRNAs) are a class of small and non-coding RNAs that negatively regulate gene expression at post-transcriptional level thus playing a role in plant growth, development, and stress response. In this study, high-throughput Illumina sequencing technology has been used to comprehensively investigate the small RNA transcriptomes of safflower seed, flower, and leaf. It is found that there are at least 236 known miRNAs expressed in safflower, of which 100 miRNAs with relatively high expression abundance exhibited evolutionary conservation across multiple plants. Comparison of their expression abundance among different tissues shows that a total of 116, 133, and 128 miRNAs are significantly differentially expressed with higher abundance or lower abundance between safflower seed/leaf, seed/petal, and leaf/petal. The majority of the most significant differences in miRNA abundance between tissues are tissue-specific miRNAs. In addition, 13 putative novel miRNAs have been identified in safflower. The small RNA transcriptomes obtained in this study provide a basis for further investigation of the physiological roles of identified miRNAs in safflower.

Design, synthesis and fungicidal activity of 11-alkoxyimino-5,6-dihydro-dibenzo[b,e] azepine-6-one derivatives.

BACKGROUND: Macrocyclic compounds with an oxime ether side chain, discovered in Wang's group, showed good fungicidal activity. However, the long synthetic route makes the cost too high for them to be developed further as practical fungicides. Alternative compounds with good fungicidal activity and an easier synthesis than the above-mentioned macrolactams were sought, and a series of 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) were designed and bioassayed. RESULTS: The structures were confirmed by (1) H NMR, (13) C NMR and LC-MS. The bioassay showed that about half of the 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) displayed good fungicidal activity against Sclerotinia sclerotiorum (Lib.) de Bary, with EC50 values <15 µg mL(-1) . 11-(n-Butyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-05), 11-(4-nitrobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-12) and 11-(2-chloro-6-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-21) displayed excellent fungicidal activity, with EC50 values of <2.5 µg mL(-1) , much better than the commercial fungicide chlorothalonil with an EC50 value of 7.16 µg mL(-1) . In addition, about half of the 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) had good fungicidal activity against Botrytis cinerea (De Bary) Whetzel, with EC50 values of <10 µg mL(-1) . 11-(2-Fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-16), 11-(3-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-17) and 11-(2-chloro-6-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-21) displayed excellent fungicidal activity, with EC50 values of 3.73, 2.54 and 3.20 µg mL(-1) respectively, comparable with the commercial fungicide procymidon with an EC50 value of 2.45 µg mL(-1) . Their structure-activity relationship is discussed. CONCLUSIONS: The present work demonstrates that the title compounds show promise as fungicides.