This work demonstrates the utilization of PTA as an acidic catalyst in primary reactions of carbohydrate. PTA can be widely used as a catalyst for carbohydrate chemistry. The reactions are executed at 0 °C or room temperature in good yields.
Epidemics caused by coronaviruses (CoVs), namely the severe acute respiratory syndrome (SARS) (2003), Middle East respiratory syndrome (MERS) (2012), and coronavirus disease 2019 (COVID-19) (2019), have triggered a global public health emergency. Drug development against CoVs is inherently arduous. The nucleocapsid (N) protein forms an oligomer and facilitates binding with the viral RNA genome, which is critical in the life cycle of the virus. In the current study, we found a potential allosteric site (Site 1) using PARS, an online allosteric site predictor, in the CoV N-N-terminal RNA-binding domain (NTD) to modulate the N protein conformation. We identified 5-hydroxyindole as the lead via molecular docking to target Site 1. We designed and synthesized four 5-hydroxyindole derivatives, named P4-1 to P4-4, based on the pose of 5-hydroxyindole in the docking model complex. Small-angle X-ray scattering (SAXS) data indicate that two 5-hydroxyindole compounds with higher hydrophobic R-groups mediate the binding between N-NTD and N-C-terminal dimerization domain (CTD) and elicit high-order oligomerization of the whole N protein. Furthermore, the crystal structures suggested that these two compounds act on this novel cavity and create a flat surface with higher hydrophobicity, which may mediate the interaction between N-NTD and N-CTD. Taken together, we discovered an allosteric binding pocket targeting small molecules that induces abnormal aggregation of the CoV N protein. These novel concepts will facilitate protein-protein interaction (PPI)-based drug design against various CoVs.
The trimethylsilyl (TMS) group is widely used in carbohydrate synthesis, although this protecting group is unstable and its post-synthetic purification challenging. The successful trimethylsilylation of carbohydrates mediated by recyclable and efficient acidic catalyst PTA/HMDS and the novel reagent, TMSOAc (TEA/TMSOAc), under alkaline condition is reported. The advantages of these methods are that the reactions proceed in good to excellent yields without applying column chromatography for purification.
This investigation describes a one‐pot reaction to prepare a series of building blocks for glycosylation reactions, such as 3‐alcohol glucosamines, fully protected glucosamines, O‐4 and O‐6 alcohol glucosamines. These reactions readily produce not only glycosyl donors and acceptors, but also different glycosyl units that can be changed based on the needs of the experiment. The synthesis of some molecules containing glucosamines, including saccharide chains of glycopeptide (GP) and precursors of lipid A disaccharide backbone, are also described. GP has good selectivity for tumor angiogenesis and this phenomenon makes the GP a potential target drug. Lipid A has recently been adopted as an adjuvant for human vaccines.
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