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Acta Pharmaceutica Sinica B 2024年第5期14卷 2349-2357页

作者： Rabea Voget Julian Breidenbach Tobias Claff Alexandra Hingst Katharina Sylvester Christian Steinebach Lan Phuong Vu Renato H.Weiße Ulrike Bartz Norbert Sträter Christa E.Müller Michael Gütschow pharmaceutical Institute Pharmaceutical&Medicinal ChemistryUniversity of BonnBonn 53121Germany Institute of Bioanalytical Chemistry Center for Biotechnology and BiomedicineLeipzig UniversityLeipzig 04103Germany department of Natural Sciences University of Applied Sciences Bonn-Rhein-SiegRheinbach 53359Germany

A titrant for the SARS-CoV-2 main protease(M^(pro))was developed that enables,for the first time,the exact determination of the concentration of the enzymatically active M^(pro) by active-site *** covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme–titrant *** fluorogenic substrates of M^(pro),including a prototypical,internally quenched Dabcyl-EDANS peptide,were compared in terms of solubility under typical assay *** exploiting the new titrant,key kinetic parameters for the M^(pro)-catalyzed cleavage of these substrates were determined.

关键词： COVID-19 SARS-CoV-2 Main protease Peptide nitriles Fluorogenic substrates Active-site titration X-ray crystallography Inner filter effect

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1457-1466页

作者： Yaqin Wei Xiangqing Xu Qiang Guo Song Zhao Yinli Qiu Dongli Wang Wenwen Yu Yani Liu KeWei Wang School of Pharmacy Xuzhou Medical UniversityXuzhou 221004China Institute of pharmaceutical research Jiangsu Nhwa Pharmaceutical Co.Ltd.&Jiangsu Key Laboratory of Central Nervous System Drug Research and DevelopmentXuzhou 221116China department of Pharmacology School of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative Drug Qingdao UniversityQingdao 266021China Center for Brain Science and Brain-Inspired Intelligence Guangdong-Hong Kong-Macao Greater Bay AreaGuangzhou 510515China

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving *** this study,we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01(a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative)that exhibits both anti-depression effects and improvements in cognition.D01 inhibits serotonin transporters(K_(i)=30.1±6.9 nmol/L)and M channels(IC_(50)=10.1±2.4μmol/L).D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on *** administrations of D01(20 and 40 mg/kg)can significantly shorten the immobility time in a mouse model of chronic restraint stress(CRS)-induced depression-like ***,D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice,but not ***,D01 reverses the long-term potentiation(LTP)inhibition induced by *** together,our findings demonstrate that D01,a dual-target serotonin reuptake and M channel inhibitor,is highly effective in the treatment-resistant depression and cognitive deficits,thus holding potential for development as therapy of depression with cognitive deficits.

关键词： SERT 5-HT Kv7/KCNQ/M current D01 Depression Cognition

The Multiple Roles of Autophagy in Neural Function and Diseases

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Neuroscience Bulletin 2024年第3期40卷 363-382页

作者： Yan-Yan Li Zheng-Hong Qin Rui Sheng department of Pharmacology and Laboratory of Aging and Nervous Diseases Jiangsu Key laboratory of Neuropsychiatric DiseasesCollege of Pharmaceutical Sciences of Soochow UniversitySuzhou 215123China

Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes,where proteins,lipids,and organelles are degraded and *** to the way the cytoplasmic components are engulfed,autophagy can be divided into macroautophagy,microautophagy,and chaperone-mediated ***,many studies have found that autophagy plays an important role in neurological diseases,including Alzheimer's disease,Parkinson's disease,Huntington's disease,neuronal excitotoxicity,and cerebral *** maintains cell homeostasis in the nervous system via degradation of misfolded proteins,elimination of damaged organelles,and regulation of apoptosis and ***-mTOR,Beclin 1,TP53,endoplasmic reticulum stress,and other signal pathways are involved in the regulation of autophagy and can be used as potential therapeutic targets for neurological ***,we discuss the role,functions,and signal pathways of autophagy in neurological diseases,which will shed light on the pathogenic mechanisms of neurological diseases and suggest novel targets for therapies.

关键词： Autophagy Neurodegenerative diseases Cerebral ischemia AMPK mTOR Beclin 1 TP53 Endoplasmic reticulum stress

Synthetic host-guest pairs as novel bioorthogonal tools for pre-targeting

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Chinese Chemical Letters 2024年第2期35卷 44-56页

作者： Yan-Long Ma Shi Yan Xiong-Jie Xu Hua Cao Ruibing Wang School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering & Technology research Center Guangdong Pharmaceutical UniversityZhongshan 528458China State Key Laboratory of Quality research in Chinese Medicine and the Institute of Chinese Medical ScienceUniversity of MacaoMacao 999078China

Due to its simplicity, high efficiency, and chemo-selectivity, bioorthogonal chemistry has shown a great application potential in ***, four bioorthogonal pairs as targeting tools, including (strept)avidin/biotin, antibody/antigen, oligonucleotide hybridization and IEDDA tools, have been developed and applied in targeted ***, all of these tools still suffer from some limitations, such as difficult modification, biochemical fragility and larger molecular weight for biological association tools, as well as chemical instability for IEDDA *** host-guest pairs with relatively small molecular sizes not only possess strong chemical stability, but also have the features of fast conjugation rate, tunable binding affinity , easy modification, and high ***, they can be used as a novel non-covalent bioorthogonal tool for *** order to further promote the development of host-guest pairs as novel bioorthogonal tools for pre-targeted delivery, we firstly calculate their conversion rate to make researcher aware of their unique advantages;next, we summarize the recent research progress in this *** future perspectives and limitations of these unique tools will be *** review will provide a systemic overview of the development of synthetic host-guest pairs as novel bioorthogonal tools for pre-targeting, and may serve as a “go for” resort for researchers who are interested in searching for new synthetic tools to improve pre-targeting.

关键词： Bioorthogonal chemistry Synthetic host-guest pairs Pre-targeting Molecular recognition Biomedical applications

CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

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Journal of pharmaceutical Analysis 2024年第6期14卷 878-888页

作者： Xinyue Cui Zhuang Hu Ruihan Li Peng Jiang Yongchang Wei Zilin Chen department of Radiation and Medical Oncology Zhongnan Hospital of Wuhan University and School of Pharmaceutical SciencesWuhan UniversityWuhan430071China Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of EducationHubei Province Engineering and Technology Research Center for Fluorinated PharmaceuticalsWuhan430071China

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the ***,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely *** carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting *** this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation ***_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S *** modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in *** also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good ***,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

关键词： CA IX-targeted Hypoxia tumor combination therapy NIR-II imaging Photothermal effect

Krüppel-like factor 2(KLF2),a potential target for neuroregeneration

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Neural Regeneration research 2024年第11期19卷 2327-2328页

作者： Surajit Hansda Prateeksha Prateeksha Hiranmoy Das department of pharmaceutical Sciences Jerry H.Hodge School of PharmacyTexas Tech University Health Sciences CenterAmarilloTXUSA

Neurological disorders and injuries lead to the impairment or depletion of neurons in terms of quantity,structure,or function,resulting in the loss of cognitive,emotional,and physical abilities in human ***,in turn,accompanies the shortfall of valuable human resources and economic potential,causing a detriment to *** these challenges,therefore,becomes imperative not only from a humanitarian perspective but also as a means of preserving human capital and bolstering economic prosperity.

关键词： companies injuries potential

Mogroside IIE,an in vivo metabolite of sweet agent,alleviates acute lung injury via Pla2g2a-EGFR inhibition

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Food Science and Human Wellness 2024年第1期13卷 299-312页

作者： Weichao Lü Guoqing Ren Kuniyoshi Shimizu Renshi Li Chaofeng Zhang State Key Laboratory of Natural Medicines School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 211198China Sino-Jan Joint Lab of Natural Health Products research School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 211198China Faculty of Agriculture Kyushu UniversityFukuoka 819-0395Japan

In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious *** IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia *** study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR *** results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by *** addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of ***2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.

关键词： Mogroside IIE Acute lung injury Secreted phospholipase A2 type IIA(Pla2g2a) Epidermal growth factor receptor(EGFR)

Piperlongumine in combination with EGFR tyrosine kinase inhibitors for the treatment of lung cancer cells

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Oncology research 2024年第11期32卷 1709-1721页

作者： SHAIL RAKESH MODI TERRICK ANDEY department of pharmaceutical Sciences Massachusetts College of Pharmacy and Health SciencesWorcesterMA 01608USA

Objectives:EGFR tyrosine kinase inhibitor(EGFR-TKI)therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer(NSCLC).However,the high incidence of acquired resistance to these EGFR-TKIs may preclude their ***(PPL),an extract from the long pepper fruit(Piper longum),has been shown to possess anticancer *** purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer ***:Anticancer efficacy of PPL,erlotinib(ERL),gefitinib(GEF),and cisplatin(CIS)were investigated in H1299 and H1975 cell *** were treated with PPL,ERL,GEF,and CIS alone,and in combination,cell viability was determined after 72 *** mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species(ROS)induction,and apoptosis induction using acridine orange/ethidium bromide staining and flow *** effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic ***:PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL,GEF,and *** treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines,which were associated with apoptotic induction,but without significant ROS *** to control,PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow *** with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular ***:PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.

关键词： Piperlongumine(PPL) Non-small cell lung cancer(NSCLC) Tyrosine kinase inhibitors(TKI) Mutation Resistance

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

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Acta Pharmaceutica Sinica B 2024年第1期14卷 207-222页

作者： Hongrui Zhu Yamin Gao Liyun Liu Mengyu Tao Xiao Lin Yijia Cheng Yaoyao Shen Haitao Xue Li Guan Huimin Zhao Li Liu Shuping Wang Fan Yang Yongjun Zhou Hongze Liao Fan Sun Houwen Lin research Center for Marine Drugs Department of PharmacyRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China department of Oncology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China Institute of Marine Drugs Guangxi University of Chinese MedicineNanning 530200China State Key Laboratory of New Drug and pharmaceutical Process Shanghai Professional and Technical Ser-vice Center for Biological Material Drug-ability EvaluationShanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 200437China Institute of Marine Biomedicine Shenzhen PolytechnicShenzhen 518055China

Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin ***,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin ***,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC ***,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

关键词： Colorectal cancer TNKSeUSP25 interaction Multi-drug resistance TNKS overexpression Wnt pathway Apoptosis Neoantimycin analog

Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 667-681页

作者： Yue Zhang Jingwen Gao Na Li Peng Xu Shimeng Qu Jinqian Cheng Mingrui Wang Xueru Li Yaheng Song Fan Xiao Xinyu Yang Jihong Liu Hao Hong Ronghao Mu Xiaotian Li Youmei Wang Hui Xu Yuan Xie Tianming Gao Guangji Wang Jiye Aa Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesResearch Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical SciencesChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Monitoring and Control Drug Intelligence and Forensic CenterMinistry of Public SecurityBeijing 100193China School of Pharmacy China Pharmaceutical UniversityNanjing 211198China School of Foreign Languages China Pharmaceutical UniversityNanjing 211198China department of Neurobiology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China department of Pharmacology China Pharmaceutical UniversityNanjing 211198China School of pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been ***,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like *** treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc *** discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower *** fast onset property of crocin was verified through multicenter ***,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on *** findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.

关键词： CAMP Nucleus accumbens Depression D1-MSN D2-MSN