Abstract: Influenza A viruses have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which leads to an urgent need to develop novel antivirals. In this study, a series of sulfonyl piperazine nucleozin derivatives were designed and synthesized, and their in vitro anti-influenza activity was evaluated. Many of these compounds exhibited moderate to good anti-influenza activity against influenza A. Among these, 6d, 6g, 6h, 6i, and 6j exhibited better activity than ribavirin. 2,3-dichlorobenzene substituted analogue 6i displayed the most remarkable in vitro activity against Influenza A. All the derivatives show no obvious cellular growth inhibition against MDCK cells. This study reported a new series of nucleoprotein inhibitors with a good selectivity window and potential for further development as novel anti-influenza agents.
Serotonin is a neurotransmitter that plays an essential regulatory role in numerous cognitive and behavioral functions. Recent advances in synthetic biology have enabled engineering of non-natural biosynthetic pathways for serotonin production in E. coli. Here, an optimized heterologous serotonin biosynthetic pathway was engineered in E. coli and coupled with the biosynthetic and regeneration modules of the endogenous vital cofactor tetrahydrobiopterin (BH4) for efficient serotonin production using whole-cell catalysis. Further metabolic engineering efforts were performed to ensure an adequate endogenous BH4 supply, including enhancements of GTP biosynthesis and intracellular reducing power availability. Using the optimized fed-batch fermentation, an overall maximum serotonin yield of 40.3% (mol/mol) and a peak titer of 1.68 g/L (production rate of 0.016 g/L/h) were achieved. The strategies employed in this study show the promise of using E. coli for pterin self-sufficiency and high-level serotonin production, and the engineered strains hold the potential for use in industrial applications.
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Abstract Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site‐specific introduction of a thioamide bond into a peptide backbone. A novel ynamide‐mediated two‐step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α‐thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH 2 , and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site‐specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.
A novel ynamide-mediated thioester synthesis strategy was developed. Importantly, no detectable racemization was observed for the thioesterifications of carboxylic acids containing an α-chiral center, enabling it to be useful for the synthesis of peptide thioester, which is the key component of native chemical ligation. It is worth mentioning that amino acid side chain functional groups such as -OH and indole -NH are compatible with the reaction conditions, rendering their protection unnecessary. Moreover, this method was also amenable to selenoesters.
Abstract An efficient heterogeneous Au/mesoporous alumina nanocatalyst has been successfully developed for the synthesis of amides and esters from simple building blocks of readily available alcohols and amines. The processes were simple and were performed at room temperature and atmospheric pressure of O 2 to form the desired products with up to 97 % isolated yield. The ability of Au/mesoporous alumina to catalyze these reactions under ambient conditions further enhances the sustainability of these chemical processes. Furthermore, the nanocatalyst was stable to air and water and could be recovered and reused easily. The enhanced catalytic activity of Au/mesoporous alumina might be attributed to the presence of negatively charged Au nanoparticles that could promote oxidation processes as well as the stability of the mesoporous alumina support calcined at a high temperature of 800 °C.
Lactococcus lactis is used extensively in cheese and fermented milk production. Acid stress is often encountered when L. lactis is used as a starter for the production of fermented foods. The effects of thiamine on the acid-stress tolerance of L. lactis were explored in this study. Exogenous thiamine improved the acid-stress tolerance of L. lactis during acid stress. When cultivated with 100 μM thiamine, the survival rate of cells was 14.2-fold higher than the control after 1.5 h of acid exposure at pH 3.8. The acid-stress responses of L. lactis mediated by thiamine were investigated by transcription level approaches. The results indicated a role for thiamine in increasing the transcription level of genes associated with acetoin biosynthesis during acid stress, which could consume more protons and maintain the relative homeostasis of intracellular pH. In addition, the transcription levels of thiamine-diphosphate-dependent enzymes were also upregulated, which provided more energy for cells to withstand acid stress. Furthermore, metabolite profiling highlighted the increased abundance of amino acid, especially glutamate, in thiamine-added cells during acid stress, and the intracellular ATP level was also improved. Finally, the production of thiamine in L. lactis was engineered, suggesting an increased acid-stress tolerance. These findings suggest that thiamine results in more excellent resistance to acid stress and could be employed as a promising protectant during probiotic fermentation.
A novel ynamide-mediated synthesis of thionoesters and dithioesters is described. The selective addition reactions of various monothiocarboxylic acids with ynamide furnish α-thioacyloxyenamides, which undergo transesterification with nucleophilic -OH or -SH species to afford thionoesters and dithioesters, respectively. The broad substrate scope, mild reaction conditions, and excellent yields make this method an attractive synthetic approach to thionoesters and dithioesters.
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