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Lipase-activated glycopeptide nano-assemblies as an antibiotic nano-adjuvant to inhibit Pseudomonas aeruginosa biofilm and enhance antibacterial activity

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Science China Chemistry 2022年第12期65卷 2538-2547页

作者： Yifei Song Jingkai Zhang Yue Fei zhangjian huang Xiaoxuan Liu Li-Li Li CAS Center for Excellence in Nanoscience CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyNational Center for Nanoscience and Technology(NCNST)Beijing100190China College of Life Science and Technology Beijing University of Chemical TechnologyBeijing100029China State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases Center of Drug DiscoveryCenter of Advanced Pharmaceutics and BiomaterialsChina Pharmaceutical UniversityNanjing210009China

Bacterial infections,especially those caused by biofilms,pose a serious threat to public health.In this work,we propose a glycopeptide-based antibiotic nano-adjuvant(GalAc-2) that can synergistically enhance the antibacterial activity of antibiotics through its biofilm inhibition activity.Our glycopeptide nanoparticles can be specifically activated by bacterial infection overexpressed lipase and sequentially enlarged by glycosyl exposure on the surface.The stability and bonding affinity of the nanoparticles were enhanced through the increase in β-sheet conformation.The bacterial growth inhibition rate of the mixture of levofloxacin(LEV) and GalAc-2 at 0.54 μg/m L was over sevenfold higher than that of LEV alone because of the electrostatic and multivalence Lec A interactions that inhibited biofilm formation on the bacterial surface.Finally,the mixture of the antibiotic with GalAc-2 significantly inhibited the abscess exposed to skin infection and significantly reduced the infiltration of immune cells.We believe that GalAc-2 can be further used to enhance broad-spectrum antibiotic sensitization and prolong the lifetime of antibiotics.

关键词： glycopeptide self-assembly antibiotic nano-adjuvant bacteria biofilm

Design and synthesis of the ring-opened derivative of 3-n-butylphthalide-ferulic acid-glucose trihybrids as potential anti-ischemic agents

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Chinese Chemical Letters 2020年第7期31卷 1881-1886页

作者： Jianbing Wu Wei Yin Yinqiu Zhang Hui Ye Yunman Li Jide Tian zhangjian huang Yihua Zhang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Drug DiscoveryChina Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Department of PhysiologyChina Pharmaceutical UniversityNanjing 210009China Department of Molecular and Medical Pharmacology University of CaliforniaLos AngelesCA 90095United States

To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB P.Additionally,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties.Importantly,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through BBB.Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.

关键词： 3-n-Butylphthalide Ferulic acid Glucose Hybrids Ischemic Brain-blood barrier

高压大功率SiC MOSFETs短路保护方法

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高电压技术 2024年第4期50卷 1583-1595页

作者：汪涛黄樟坚虞晓阳张茂强骆仁松李响南京南瑞继保电气有限公司南京211102

碳化硅(SiC)MOSFETs短路承受能力弱,研究其短路保护方法成为保障电力电子设备安全运行的重要课题。现有方法大多围绕低压小功率SiC MOSFETs,然而随着电压和功率等级的提升,器件特性有所差异,直接套用以往设计难以实现高压大功率SiC MOSF... 详细信息

碳化硅(SiC)MOSFETs短路承受能力弱,研究其短路保护方法成为保障电力电子设备安全运行的重要课题。现有方法大多围绕低压小功率SiC MOSFETs,然而随着电压和功率等级的提升,器件特性有所差异,直接套用以往设计难以实现高压大功率SiC MOSFETs的快速、可靠保护。该文首先详细研究了几种常用短路检测方法;其次基于高压大功率SiC MOSFETs器件特性,深入对比分析了不同短路检测方法的适用性,提出一种阻容式漏源极电压检测和栅极电荷检测相结合的短路保护方法;最后搭建了实验平台验证所提方法的可行性。结果表明,提出的方法在硬开关短路故障(hard switching fault,HSF)下,保护响应时间缩短了1.4μs,短路能量降低了62.5%;且能可靠识别负载短路故障(fault under load,FUL)。

关键词： SiC MOSFETs 高压大功率短路保护器件特性漏源极电压栅极电荷

A novel PGAM5 inhibitor LFHP-1c protects bloodebrain barrier integrity in ischemic stroke

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1867-1884页

作者： Chenglong Gao Yazhou Xu Zhuangzhuang Liang Yunjie Wang Qinghong Shang Shengbin Zhang Cunfang Wang Mingmin Ni Dalei Wu zhangjian huang Tao Pang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningJiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Helmholtz International Lab State Key Laboratory of Microbial TechnologyShandong UniversityQingdao 266237China Guangdong Long Fu Pharmaceutical Co. Ltd.Zhongshan 528451China Key Laboratory of Drug Quality Control and Pharmacovigilance(China Pharmaceutical University) Ministry of EducationNanjing 210009China

Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains unknown.Here,we show that LFHP-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity,but also reduced the interaction of PGAM5 with NRF2,which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia.Furthermore,LFHP-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.

关键词： Ischemic stroke Bloodebrain barrier Brain microvascular endothelial cells Target identification Surface plasmon resonance PGAM5 NRF2 LFHP-1c

New techniques and strategies in drug discovery

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Chinese Chemical Letters 2020年第7期31卷 1695-1708页

作者： Jintong Du Jing Guo Dongwei Kang Zhihong Li Guan Wang Jianbing Wu Zhen Zhang Hao Fang Xuben Hou zhangjian huang Guobo Li Xiaoyun Lu Xinyong Liu Liang Ouyang Li Rao Peng Zhan Xiaojin Zhang Yihua Zhang Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical SciencesJi'nan 250117China School of Pharmacy Ji'nan UniversityGuangzhou 510632China Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJi'nan 250012China Department of Chemistry Jiangsu Key Laboratory of Drug Design and OptimizationChina Pharmaceutical UniversityNanjing 211198China Stare Key Laboratory of Biotherapy and Cancer Center West China Hospitaland Collaborative Innovation Center of BiotherapySichuan UniversityChengdu 610041China Stare Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education West China School of PharmacySichuan UniversityChengdu 610041China Key Laboratory of Pesticide&Chemical Biology(CCNU) Ministry of EducationDepartment of ChemistryCentral China Normal UniversityWuhan 430079China

Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding poses.Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action studies.Current and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging progress.However,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire process.This part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine residues.Recent studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase activities.Here,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on its concentration,optimal levels of NO in cance

关键词： Protein-ligand binding structure Target profiling In silico autophagy method Defatty-acylase Allosteric kinase inhibitor Drug resistance Nitric oxide donor Photoactivation strategies

羧甲司坦L-精氨酸盐的合成及其对支气管上皮细胞的保护作用

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中国药科大学学报 2022年第2期53卷 171-177页

作者：贾健吴建兵张奕华黄张建中国药科大学新药研究中心南京210009

羧甲司坦(CMC)是治疗慢性阻塞性肺病的常用药,长期服用对胃肠道产生严重刺激。L-精氨酸是一氧化氮(NO)合酶(NOS)的底物,在体内可转化为对心血管及胃肠道等有益的NO。L-精氨酸属碱性氨基酸,能与某些含羧酸基团的化合物成盐以改善原药的... 详细信息

羧甲司坦(CMC)是治疗慢性阻塞性肺病的常用药,长期服用对胃肠道产生严重刺激。L-精氨酸是一氧化氮(NO)合酶(NOS)的底物,在体内可转化为对心血管及胃肠道等有益的NO。L-精氨酸属碱性氨基酸,能与某些含羧酸基团的化合物成盐以改善原药的水溶性,并可能由于促进NO的释放带来活性的提高或毒副作用的缓解。因此,本文设计、合成了CMC的L-精氨酸盐(CMCA),并测试其理化性质以及在香烟烟雾诱导的人支气管上皮细胞损伤模型中清除活性氧(ROS)、抗细胞凋亡和NO释放的能力。结果表明,CMCA能有效捕获ROS,释放NO,并抑制细胞凋亡,效果优于CMC或L-精氨酸,提示该化合物值得深入研究和开发。

关键词：慢性阻塞性肺疾病羧甲司坦一氧化氮 L-精氨酸活性氧凋亡

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四价铂前药研究现状与进展

中国药科大学学报 2022年第5期53卷 613-622页

作者：朱杰张宸吴建兵张奕华黄张建中国药科大学新药研究中心南京210009

以顺铂为代表的二价铂[Pt(Ⅱ)]类药物是现在活跃于一线的抗肿瘤药物,但Pt(Ⅱ)类药物存在不良反应大、生物利用度不佳以及耐药性等问题。四价铂[Pt(Ⅳ)]络合物是Pt(Ⅱ)在轴向位置进行不同取代的衍生物,在肿瘤还原性物质的作用下Pt(Ⅳ)可... 详细信息

以顺铂为代表的二价铂[Pt(Ⅱ)]类药物是现在活跃于一线的抗肿瘤药物,但Pt(Ⅱ)类药物存在不良反应大、生物利用度不佳以及耐药性等问题。四价铂[Pt(Ⅳ)]络合物是Pt(Ⅱ)在轴向位置进行不同取代的衍生物,在肿瘤还原性物质的作用下Pt(Ⅳ)可被还原为Pt(Ⅱ),因此Pt(Ⅳ)可作为Pt(Ⅱ)的前药。Pt(Ⅳ)中轴向取代基的引入可改善Pt(Ⅱ)类药物的药代动力学性质、选择性和生物活性,以及实现除DNA交联之外的附加细胞毒机制,可一定程度上克服Pt(Ⅱ)类药物的耐药性。本文归纳总结了铂类药物的耐药机制,包括铂转运增加、解毒能力增加、自噬增强和DNA修复增强等方面;综述了Pt(Ⅳ)前药的构效关系、主要类型及研究进展,并提出了克服铂类药物耐药性的可能途径。

关键词：四价铂前药顺铂抗肿瘤耐药性

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考虑死区效应的双有源桥直流变压器损耗优化

电力系统自动化 2023年第6期47卷 197-205页

作者：汪涛骆仁松张茂强黄樟坚王子龙李响南京南瑞继保电气有限公司江苏省南京市211102

死区效应导致双有源桥(DAB)变换器的功率传输特性及零电压开通运行范围偏离理想模型,建立考虑死区效应的稳态模型对DAB优化控制具有重要意义。文中详细分析了死区中的电路模态以及模态间的转换过程,提出基于状态机的死区计算模型,实现了... 详细信息

死区效应导致双有源桥(DAB)变换器的功率传输特性及零电压开通运行范围偏离理想模型,建立考虑死区效应的稳态模型对DAB优化控制具有重要意义。文中详细分析了死区中的电路模态以及模态间的转换过程,提出基于状态机的死区计算模型,实现了SiC MOSFET不完全零电压开通现象的定量分析。提出基于离散时间序列方法的DAB稳态计算模型,降低了建模复杂性,实现了三重移相控制下死区状态的准确计算。受益于DAB稳态模型的计算速度,基于参数遍历优化方法实现2 kV/150 kW直流变压器模块的全工况损耗最优控制。采用3.3 kV碳化硅器件搭建了150 kW直流变压器模块样机,在损耗最优控制策略下10%至100%功率范围内的效率大于98.0%,峰值效率达到99.3%。

关键词：直流变压器双有源桥死区效应损耗优化

吸入CDDO-NO对野百合碱诱导的大鼠肺动脉高压的作用

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南京医科大学学报（自然科学版） 2022年第9期42卷 1201-1208页

作者：伍雪橙李南黄文周淑兰周宏黄张建孔辉解卫平南京医科大学第一附属医院呼吸与危重症医学科江苏南京210029 中国药科大学新药研究中心天然药物活性组分与药效国家重点实验室江苏南京210009

目的:研究吸入新型一氧化氮供体型甲基巴多索隆(bardoxolone methyl,CDDO-Me)衍生物CDDO-NO对野百合碱(monocrotaline,MCT)诱导大鼠肺动脉高压(pulmonary arterial hypertension,PAH)的作用。方法:SD雄性大鼠随机分为6组,对照组(Con组)、MCT组、MCT+10μg/kg CDDO-NO组(MCT+10NO组)、MCT+30μg/kg CDDO-NO组(MCT+30NO组),以及MCT+7μg/kg CDDO-Me组(MCT+7Me组)和MCT+21μg/kg CDDO-Me组(MCT+21Me组)。MCT组及各治疗组均给予60 mg/kg MCT腹腔注射造模,CDDO-NO及CDDO-Me治疗组在MCT注射1 h后通过口鼻暴露式雾化吸入装置给药。连续雾化吸入给药28 d后,右心导管测量大鼠右心室收缩压(right ventricular systolic pressure,RVSP),计算右心室肥厚指数(right ventricular hypertrophy index,RVHI)和大鼠右室/体重比(RV-to-body weight ratio,RV/BW)。苏木素伊红(hematoxylin-eosin,HE)染色检测肺小动脉中膜层厚度(pulmonary artery medial thickness,PAMT)及右心室心肌细胞横截面积(cross-sectional area,CSA),马松三色染色(masson trichrome staining,MTS)评估肺小动脉周围纤维化程度,α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)免疫组化染色检测肺小动脉肌化程度。结果:血流动力学及右室重构指标显示,吸入CDDO-NO或CDDO-Me均可降低MCT诱导PAH大鼠的RVSP、RVHI和RV/BW升高,其中30μg/kg CDDO-NO降低RVHI和RV/BW的效应优于等量母体化合物CDDO-Me(21μg/kg)。此外,病理学研究显示,吸入30μg/kg CDDO-NO改善MCT诱导的PAH模型大鼠右室心肌细胞肥大和肺血管中膜层肥厚、降低完全肌化型血管比例及肺血管外膜胶原沉积的效果较等量母体化合物CDDO-Me(21μg/kg)更佳。结论:吸入CDDO-NO可通过抑制肺血管重构减轻MCT诱导的大鼠PAH,效果优于母体化合物CDDO-Me,是一种治疗PAH的潜在化合物。

关键词：肺动脉高压 CDDO-NO 肺血管重构