VI-116, A Novel Potent Inhibitor of VRAC with Minimal Effect on ANO1

Volume-regulated anion channel (VRAC) is ubiquitously expressed and plays a pivotal role in vertebrate cell volume regulation. A heterologous complex of leucine-rich repeat containing 8A (LRRC8A) and LRRC8B-E constitutes the VRAC, which is involved in various processes such as cell proliferation, migration, differentiation, intercellular communication, and apoptosis. However, the lack of a potent and selective inhibitor of VRAC limits VRAC-related physiological and pathophysiological studies, and most previous VRAC inhibitors strongly blocked the calcium-activated chloride channel, anoctamin 1 (ANO1). In the present study, we performed a cell-based screening for the identification of potent and selective VRAC inhibitors. Screening of 55,000 drug-like small-molecules and subsequent chemical modification revealed 3,3′-((2-hydroxy-3-methoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (VI-116), a novel potent inhibitor of VRAC. VI-116 fully inhibited VRAC-mediated I⁻ quenching with an IC₅₀ of 1.27 ± 0.18 μM in LN215 cells and potently blocked endogenous VRAC activity in PC3, HT29 and HeLa cells in a dose-dependent manner. Notably, VI-116 had no effect on intracellular calcium signaling up to 10 μM, which completely inhibited VRAC, and showed high selectivity for VRAC compared to ANO1 and ANO2. However, DCPIB, a VRAC inhibitor, significantly affected ATP-induced increases in intracellular calcium levels and Eact-induced ANO1 activation. In addition, VI-116 showed minimal effect on hERG K⁺ channel activity up to 10 μM. These results indicate that VI-116 is a potent and selective VRAC inhibitor and a useful research tool for pharmacological dissection of VRAC.     

Cocaprins, β-Trefoil Fold Inhibitors of Cysteine and Aspartic Proteases from Coprinopsis cinerea

We introduce a new family of fungal protease inhibitors with β-trefoil fold from the mushroom Coprinopsis cinerea, named cocaprins, which inhibit both cysteine and aspartic proteases. Two cocaprin-encoding genes are differentially expressed in fungal tissues. One is highly transcribed in vegetative mycelium and the other in the stipes of mature fruiting bodies. Cocaprins are small proteins (15 kDa) with acidic isoelectric points that form dimers. The three-dimensional structure of cocaprin 1 showed similarity to fungal β-trefoil lectins. Cocaprins inhibit plant C1 family cysteine proteases with K_i in the micromolar range, but do not inhibit the C13 family protease legumain, which distinguishes them from mycocypins. Cocaprins also inhibit the aspartic protease pepsin with K_i in the low micromolar range. Mutagenesis revealed that the β2-β3 loop is involved in the inhibition of cysteine proteases and that the inhibitory reactive sites for aspartic and cysteine proteases are located at different positions on the protein. Their biological function is thought to be the regulation of endogenous proteolytic activities or in defense against fungal antagonists. Cocaprins are the first characterized aspartic protease inhibitors with β-trefoil fold from fungi, and demonstrate the incredible plasticity of loop functionalization in fungal proteins with β-trefoil fold.     

Recent Advances in Application of Computer-Aided Drug Design in Anti-Influenza A Virus Drug Discovery

Influenza A is an acute respiratory infectious disease caused by the influenza A virus, which seriously threatens global human health and causes substantial economic losses every year. With the emergence of new viral strains, anti-influenza drugs remain the most effective treatment for influenza A. Research on traditional, innovative small-molecule drugs faces many challenges, while computer-aided drug design (CADD) offers opportunities for the rapid and effective development of innovative drugs. This literature review describes the general process of CADD, the viral proteins that play an essential role in the life cycle of the influenza A virus and can be used as therapeutic targets for anti-influenza drugs, and examples of drug screening of viral target proteins by applying the CADD approach. Finally, the main limitations of current CADD strategies in anti-influenza drug discovery and the field’s future directions are discussed.     

脲醛树脂/TiO2复合微球缓蚀剂的制备及性能表征

为降低发射药的烧蚀性,在不引入模板剂和结构导向剂的情况下,控制尿素和甲醛逐步聚合得到一种表面多孔的脲醛树脂微球作为基体,用溶胶-回流法在孔上沉积纳米TiO_2颗粒,形成复合微球作为缓蚀添加剂使用。扫描电镜及粒径分析结果表明脲醛树脂微球表面存在明显的斑驳纳米孔,结合傅里叶红外(FT-IR)和光电子能谱(XPS)分析,确定纳米孔可用于沉积纯度较高的纳米TiO_2,形成的脲醛树脂/TiO_2复合微球粒径分布在7～30μm。热分析结果显示,复合微球中无机组分的含量约为6%,复合微球与发射药具有良好的相容性,不会影响发射药的热分解且有利于提高发射药的热安定性。半密闭爆发器试验证实了复合微球的缓蚀性能,当复合微球相对于发射药的质量占比为3.4%时效果最好,缓蚀效率可达20.5%。该复合材料有望应用于制式发射药改性和新型高能发射药设计。     

基于 EPDM 热解材料的力学性能研究

为研究固体火箭发动机包覆层材料在不同热解程度下的微观结构和力学行为,通过热重分析得到三元乙丙（ EPDM）包覆层的热解温度范围。分别对不同热解温度下的EPDM试件进行力学实验和电镜扫描,并从微观角度分析材料力学行为发生变化的原因。结果表明：在初始热解程度下,材料只是发生了少量的失水和气体的逃逸,其力学行为仍属于粘超弹材料范畴;随着材料热解程度的增加,部分材料基体发生裂解,其力学行为表现为脆性材料特性。     

硫酸钡防垢剂FBR的合成与性能评价

以顺丁烯二酸酐、丙烯酸和丙烯酸甲酯为原料进行共聚反应,制备了防垢剂FBR.考察了防垢剂加量、温度、防垢时间、体系pH值及矿化度对防垢性能的影响.结果表明,在70 ℃下防垢时间为16 h时防垢率在97%以上,80 ℃下防垢率仍可达95%以上;在高成垢离子浓度条件下,FBR仍具有较好的防垢能力.     

酸性气田连续油管作业防硫缓蚀剂研究与应用

针对酸性气田连续油管作业,在高温高压强酸性环境下,连续油管不可避免的受到湿H 2S腐蚀,导致连续油管性能退化,引起穿孔、氢脆及断裂等现象,连续油管使用寿命明显缩短.通过实验评价,研选出了咪唑啉类A-283防腐缓蚀剂作为连续油管在酸性气田环境下作业用缓蚀剂,在100℃、70 MPa、5000 mm/s的17.5％H2S气...     

含钠磷酸盐对煤自燃抑制性能研究

为了探究含钠磷酸盐阻化剂对煤自燃氧化反应的抑制作用,以气煤作为实验煤样,选取磷酸二氢钠NaH₂PO₄和磷酸钠Na₃PO₄ 2种含钠磷酸盐化合物制备阻化剂。采用同步热分析实验和程序升温氧化实验分析含钠磷酸盐对煤自燃过程中热失重、热释放,以及气相特性的影响。结果表明:当煤自燃达到热解温度后,Na₃PO₄不再具有阻化作用;NaH₂PO₄可显著提高煤自燃的临界温度、干裂温度、着火温度等,此外,NaH₂PO₄有效提高了煤自燃初始放热温度和最大释热温度,且降低了煤自燃最大释热功率和放热量;NaH₂PO₄能够提高煤自燃过程中CO、CO₂及各烃类气体的初始生成温度,削弱其释放强度,其阻化率可达65.4%;相比于Na₃PO₄阻化剂,NaH₂PO₄阻化剂具有更好的阻化效果,且在煤自燃氧化全过程中均发挥了抑制作用。     

新型凝胶泡沫材料阻化性能实验研究

为研究新型凝胶泡沫对煤体阻化作用的效能与影响,基于程序升温实验,对凝胶泡沫处理前后的不同粒径煤样组进行实验,分析煤样升温过程中的耗氧速率、CO与CH₄气体体积分数及其产生率,以及凝胶泡沫对煤样的阻化率。研究结果表明：煤的粒径不同,其耗氧速率也不同,经新型凝胶泡沫处理煤样的CO、CH₄气体的体积分数及其产生率均明显低于未经处理的煤样;在100 ℃时,粒径小于0.9 mm煤样的阻化率为59.23%,粒径3~5 mm煤样的阻化率为61.69%,粒径6~10 mm煤样的阻化率为65.63%,各粒径煤样受凝胶泡沫的阻化影响顺序为大粒径> 中粒径> 小粒径;新型凝胶泡沫材料能有效延缓煤的氧化过程、抑制煤氧复合反应、延迟煤体蓄热进程,对防治煤自燃具有十分积极的作用。     

某混合粗精矿铜铅分离选矿试验研究

混合粗精矿Cu品位8.51%、Pb品位15.23%;样品中黄铜矿、方铅矿包裹体较多,粒度较细,针对该样品性质,主要从浮选、重选角度进行铜铅分离试验研究,最终推荐粗精矿精选—铜铅分离(抑铅浮铜)—重选提高铅品位联合工艺流程;抑铅浮铜工艺采用自行设计的无氰、低铬、无污染组合抑制剂RBT-2,使铜、铅达到有效分离;最终可获得Cu品位21.50%、含Pb 4.57%、Cu回收率69.92%的铜精矿;Pb品位46.89%、含Cu 0.82%、Pb回收率55.39%的铅精矿。此流程中重选提高铅精矿品位工艺,使铅矿物得以富集,分离效果明显,获得了Pb品位大于40%的铅精矿。