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Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4945-4962页

作者： Xintong Zhao Jing Feng Jie Zhang Zunsheng Han Yuhua Hu Hui-Hui Shao Tianlei Li Jie Xia Kangfan Lei Weiping Wang Fangfang Lai Yuan Lin Bo Liu Kun Zhang Chi Zhang Qingyun Yang Xinyu Luo Hanyilan Zhang Chuang Li Wenxuan Zhang Song Wu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial *** we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AzD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial *** hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase(GyrB,IC_(50)=49 nmol/L)and a modest inhibitory effect on TopoⅣ(ParE,IC_(50)=1.513μmol/L)of Staphylococcus *** also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration(MIC)of less than 0.03μg/mL,which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against *** 28 had better protective effects than the positive control drugs such as DS-2969(5)and AZD5099(6)in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus(MRSA)*** also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection ***,compound 28 has much lower mitochondrial toxicity than AZD5099(6)as well as excellent therapeutic indexes and pharmacokinetic *** present,compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial *** the other hand,compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli(MIC=1μg/mL),which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported *** addition,the structure-activity relationships of the compounds were also studied.

关键词： GyrB/ParE inhibitor Anti-bacterial infection Structural modifications Druggability evaluation

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Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

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Journal of Pharmaceutical Analysis 2023年第9期13卷 1024-1040页

作者： Hang Yu Hui Xu Xinyu Yang Zhengwei Zhang Jiachun Hu Jinyue Lu Jie Fu Mengmeng Bu Haojian Zhang Zhao Zhai Jingyue Wang Jiandong Jiang Yan Wang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences/Peking Union Medical CollegeBeijing100050China

Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has antiinflammation,anti-oxidation,and anti-tumor *** low bioavailability makes it difficult to explain the mechanism of pharmacological effect of *** this study,the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were *** can be rapidly metabolized by the gut microbiome,and two intestinal bacterial metabolites of SNZ,salidroside and tyrosol,were *** addition,carboxylesterase may be the main intestinal bacterial enzyme that mediates its *** the same time,no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate,indicating that the gut microbiota is the main part involved in the metabolism of *** addition,pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut ***,tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ,which indicated that SNZ exhibited potential to inhibit tumor growth,and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor *** the same time,SNZ modulated the structure of gut microbiota and fungal group,which may be the mechanism governing the antitumoral activity of ***,SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in *** the future,targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.

关键词： Specnuezhenide Pharmacokinetics Tumor Gut microbiota Fungi Metabolism

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The toxic natural product tutin causes epileptic seizures in mice by activating calcineurin

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1916-1925页

作者： Qing-Tong Han Wan-Qi Yang Caixia Zang Linchao Zhou Chong-Jing Zhang Xiuqi Bao Jie Cai Fangfei Li Qinyan Shi Xiao-Liang Wang Jing Qu Dan Zhang Shi-Shan Yu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China

Tutin,an established toxic natural product that causes epilepsy in rodents,is often used as a tool to develop animal model of acute epileptic ***,the molecular target and toxic mechanism of tutin were *** this study,for the first time,we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome *** studies showed that calcineurin(CN)was a target of tutin,and that tutin activated CN,leading to *** site studies further established that tutin bound within the active site of CN catalytic *** inhibitor and calcineurin A(CNA)knockdown experiments in vivo proved that tutin induced epilepsy by activating CN,and produced obvious nerve ***,these findings revealed that tutin caused epileptic seizures by activating ***,further mechanism studies found that N-methyl-D-aspartate(NMDA)receptors,gammaaminobutyric acid(GABA)receptors and voltage-and Ca2+-activated K+(BK)channels might be involved in related signaling *** study fully explains the convulsive mechanism of tutin,which provides new ideas for epilepsy treatment and drug development.

关键词： epilepsy seizures epileptic

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Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

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Chinese Chemical Letters 2023年第2期34卷 434-439页

作者： Ruxuan Wang Rentao Zhang Haoran Yang Nina Xue Xiaoguang Chen Xiaoming Yu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Heat shock protein 90(Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin(GA) is the first identified Hsp90 inhibitor that exhibited potent anticancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1(C6-ethyl) and 2(C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds1 and 2 bind to Hsp90 protein with the IC_(50) of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.

关键词： Hsp90 inhibitors Geldanamycin derivatives Total synthesis Structure-activity relationship Anticancer

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functional characterization of a cycloartenol synthase and four glycosyltransferases in the biosynthesis of cycloastragenol-type astragalosides from Astragalus membranaceus

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Acta Pharmaceutica Sinica B 2023年第1期13卷 271-283页

作者： Yangyang Duan Wenyu Du Zhijun Song Ridao Chen Kebo Xie Jimei Liu Dawei Chen Jungui Dai State Key Laboratory of Bioactive Substance and Function of Natural Medicines CAMS Key Laboratory of Enzyme and Biocatalysis of Natural DrugsNHC Key Laboratory of Biosynthesis of Natural ProductsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Astragalosides are the main active constituents of traditional Chinese medicine Huang-Qi,of which cycloastragenol-type glycosides are the most typical and major bioactive *** kind of compounds exhibit various biological functions including cardiovascular protective,neuroprotective,*** to the limitations of natural sources and the difficulties encountered in chemical synthesis,re-engineering of biosynthetic machinery will offer an alternative and promising approach to producing ***,the biosynthetic pathway for astragalosides remains elusive due to their complex structures and numerous reaction types and ***,guided by transcriptome and phylogenetic analyses,a cycloartenol synthase and four glycosyltransferases catalyzing the committed steps in the biosynthesis of such bioactive astragalosides were functionally characterized from Astragalus ***1,the first reported cycloartenol synthase from Astragalus genus,is capable of catalyzing the formation of cycloartenol;AmUGT15,AmUGT14,AmUGT13,and AmUGT7 are four glycosyltransferases biochemically characterized to catalyze 3-O-xylosylation,3-O-glucosylation,25-O-glucosylation/O-xylosylation and 2’-O-glucosylation of cycloastragenol glycosides,*** findings not only clarified the crucial enzymes for the biosynthesis and the molecular basis for the structural diversity of astragalosides in Astragalus plants,also paved the way for further completely deciphering the biosynthetic pathway and constructing an artificial pathway for their efficient production.

关键词： Cycloastragenol-type astragalosides Cycloartenol synthase Glycosyltransferase Biosynthesis Astragalus membranaceus

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Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1771-1785页

作者： Yuyu Liu Xinnan Li Songyang Sui Jingshu Tang Dawei Chen Yuying Kang Kebo Xie Jimei Liu Jiaqi Lan Lei Wu Ridao Chen Ying Peng Jungui Dai State Key Laboratory of Bioactive Substance and Function of Natural Medicines CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugsand NHC Key Laboratory of Biosynthesis of Natural ProductsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Bibenzyls,a kind of important plant polyphenols,have attracted growing attention for their broad and remarkable pharmacological ***,due to the low abundance in nature,uncontrollable and environmentally unfriendly chemical synthesis processes,these compounds are not readily ***,one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic *** types of efficiently postmodifying modular strains were engineered by employing methyltransferases,prenyltransferase,and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic *** different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination ***,a prenylated bibenzyl derivative(12)was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia ***-seq,quantitative RT-PCR,and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor,mitochondria associated 3(Aifm3),suggesting that Aifm3 might be a new target in ischemic stroke *** study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.

关键词： Bibenzyls Modular co-culture engineering Promiscuous enzymes Neuroprotective agent Aifm3 Dendrobium officinale

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JAK inhibition ameliorated experimental autoimmune encephalomyelitis by blocking GM-CSF-driven inflammatory signature of monocytes

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Acta Pharmaceutica Sinica B 2023年第10期13卷 4185-4201页

作者： Shuai Shao Chengjuan Chen Gaona Shi Yu Zhou Yazi Wei Lei Wu Lan Sun Tiantai Zhang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system(CNS)due to the critical roles of these cells in the production of proinflammatory cytokines,differentiation of T-helper(Th)cells,and antigen *** JAK-STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines ***,the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis(MS)is ***,we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis(EAE),a model for *** inhibition prevented the CNS-infiltrating CCR2-dependent Ly6^(Chi)monocytes and monocyte-derived dendritic cells in EAE *** parallel,the proportion of GM-CSF^(+)CD4^(+)T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition,which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue ***,our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes.

关键词： Monocytes T-helper cells Monocyte-derived dendritic cells GM-CSF JAK-STAT signaling JAK inhibitor Experimental autoimmune encephalomyelitis Multiple sclerosis

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Chemoproteomics identifies Ykt6 as the direct target of schisandrin A for neuroprotection

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Chinese Chemical Letters 2023年第6期34卷 401-405页

作者： Tiantian Wang Yu Zhou Hao Zheng Tao Shen Dongmei Wang Jinlan Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Schisandrin A is a natural dibenzocyclooctene lignan with potent neuroprotective ***,the specific mechanisms or direct target proteins have not been clarified up to *** this study,we designed and synthesized the probes of schisandrin A with photoreactive diazirine and clickable alkyne to identify its direct target in SH-SY5Y cells by employing activity-based protein profiling(ABPP)***6 was prominent among the 13 proteins obtained with high confidence and we confirmed Ykt6 as the direct target of schisandrin A by CETSA,IF,SPR and knockdown ***,schisandrin A protected the cells against the injury induced by glutamate by regulating autophagy via *** discovery may provide a novel therapeutic option for various neuronal cell damage-mediated diseases.

关键词： Schisandrin A Activity-based protein profiling(ABPP) Neuroprotection Ykt6 Autophagy

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ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4733-4747页

作者： Mingjin Wang Weida Wang Shen You Zhenyan Hou Ming Ji Nina Xue Tingting Du Xiaoguang Chen Jing Jin Department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor *** is closely related to the function of myeloid ***,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM *** investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of *** results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and *** mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

关键词： Glioblastoma Myeloid cells Myeloid-derived suppressor cells Acetyl-CoA acetyltransferase 1 CXCL1 Tumor microenvironment Lipid metabolism Macrophages

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Pairs of thiol-substituted 1,2,4-triazole-based isomeric covalent inhibitors with tunable reactivity and selectivity

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Chinese Chemical Letters 2024年第7期35卷 329-335页

作者： Shiqi Xu Zi Ye Shuang Shang Fengge Wang Huan Zhang Lianguo Chen Hao Lin Chen Chen Fang Hua Chong-Jing Zhang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Beijing Key Laboratory of Active Substance Discovery and Druggability EvaluationInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000China

Covalent bioactive compounds are successfully used in clinic and attracted intense research efforts in the fundamental study as well as drug *** advantageous effects of covalent compounds compared with non-covalent ones are highly dependent on electrophilic ***,electrophilic warheads with tunable reactivity and selectivity are highly demanded in fields of medicinal chemistry and chemical ***,we report a novel electrophilic warhead,chloromethyl group activated by thiol-substituted 1,2,***,a pair of regioisomers could be simultaneously occurred in the step of alkylation during the synthesis of this unique *** is a rare example that the alkylation could simultaneously generate these two separable regioisomers of 1,2,4-triazole at the nitrogen or sulfur *** covalent-working mechanism of this new warhead is confirmed by various chemoproteomics experiments including target identification and binding site ***,the reactivity and selectivity of this new electrophilic warhead could be efficiently tuned by virtue of stereo ***,one pair of regioisomers(19S and 19X)induced distinct modes of cell *** 19S could induce apoptosis of colon cancer cells while 19X could induce both apoptosis and ***,this study provides pairs of novel electrophilic warheads that could be useful not only in supporting the design of covalent compounds for drug discovery but also in providing chemical probes for the fundamental biological study.

关键词： Electrophilic warhead Covalent inhibitor 1,2,4-Triazole Chemical proteomics GSTO1

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