Discovery of novel PTP1B inhibitors via pharmacophore-oriented scaffold hopping from Ertiprotafib

An integrated molecular design strategy combining pharmacophore recognition and scaffold hopping was exploited to discover novel PTP1B inhibitors based on the known PTP1B inhibitor Ertiprotafib. A composite pharmacophore model was proposed from the interaction mode of Ertiprotafib, and 21 diverse molecules from five distinct structural classes were designed and synthesized accordingly. New compounds with considerable inhibition against PTP1B were identified from each series, and the most active compound 3a showed IC₅₀ value of 1.3 μmol L^?1 against human recombinant PTP1B. Docking study indicated that the new inhibitors assumed binding modes similar to that of Ertiprotafib.     

PIAS1对PRRSV N蛋白SUMO化修饰及病毒复制的影响

【目的】猪繁殖与呼吸综合征病毒(PRRSV)是一种危害全球养猪业的重要病原。SUMO(Small ubiquitin-like modifier)化修饰作为一种可逆的翻译后修饰在调节病毒复制方面发挥着重要功能。PIAS1(Protein inhibitor of activated STAT1)是SUMO E3连接酶PIAS家族的一员,可以促进靶蛋白的SUMO化修饰,进而影响靶蛋白的功能,参与基因转录调控过程。探究PIAS1与PRRSV N蛋白相互作用的机制及其对N蛋白SUMO化修饰和病毒复制的影响,为进一步阐明PRRSV复制调控和致病的分子机制提供科学依据。【方法】利用酵母回复杂交、免疫共沉淀和激光共聚焦技术验证N蛋白与PIAS1的相互作用;以递增剂量外源性转染PIAS1观察其是否介导N蛋白SUMO化修饰;采用RNA干扰和慢病毒转导技术测定PIAS1对PRRSV复制的影响。【结果】PIAS1能与N蛋白相互作用,而且两者主要共定位于胞浆中;外源转染PIAS1并未增加N蛋白SUMO化修饰水平;在MARC-145细胞中,PIAS1的表达有利于PRRSV的复制。【结论】PIAS1可促进PRRSV的复制。     

Functional transplantation of the sumoylation machinery into Escherichia coli

Modification by SUMO proteins appears to be very common in eukaryotic cells. Many proteins have been reported to be sumoylated, at least under certain circumstances, in vivo, and new examples get published every month. On the other hand, sumoylation is, in essence, a way to construct branched proteins or protein fusions. Obtention of pure sumoylated proteins from eukaryotic cells is not easy because of the dynamic nature of this modification and the large number of sumoylated proteins in vivo. Production of sumoylated proteins in vitro requires the previous purification of most of the components of the pathway, and has the typical limitations of such systems. In this paper, we describe a method to quantitatively produce sumoylated proteins in vivo in Escherichia coli as a way to obtain large quantities of specifically sumoylated target proteins with a high degree of purity, to generate fusion proteins not limited to N- or C-end additions, and to polymerize proteins by covalent linkage.