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Cytotoxic and antibacterial substances against multi-drug resistant pathogens from marine sponge symbiont:Citrinin,a secondary metabolite of Penicillium sp.

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Asian Pacific Journal of Tropical biomedicine 2013年第4期3卷 291-296页

作者： Ramesh Subramani Rohitesh Kumar Pritesh Prasad William Aalbersberg Centre for drug discovery and Conservation Institute of Applied SciencesThe University of the South Pacific.Laucala CampusSuva.Fiji Islands

Objective:To Isolate,purify,characterize,and evaluate the bioaclive compounds from the sponge-derived fungus Penicillium ***001 and to elucidate its ***:The fungal strain FF001 with an interesting bioactivity profile was isolated from a marine Fijian sponge Melophlus *** on conidiophores aggregation,conidia development and mycelia morphological characteristics,the isolate FF001 was classically identified as a Penicillium *** bioactive compound was identified using various spectral analysis of UV,high resolution electrospray ionization mass spectra,1H and 13C NMR spectral *** minimum inhibitory concentrations(MICs)assay and brine shrimp cytotoxicity assay were also carried out to evaluate the biological properties of the purified ***:Bioassay guided fractionation of the EtOAc extract of a static culture of this Penicillium *** different chromatographic methods led the isolation of an antibacterial,anticryptococcal and cytotoxic active compound,which was identified as citrinin(1).Further,citrinin(1)is reported for its potent antibacterial activity against methicillin-resistant Staphylococcus aureus(***),rifampicin-resistant ***,wild type *** and vancomycin-resistant Enterococcus faecium showed MICs of 3.90,0.97,1.95 and7.81μg/mL,*** citrinin(1)displayed significant activity against the pathogenic yeast Cryptococcus neoformans(MIC 3.90μg/mL),and exhibited cytotoxicity against brine shrimp larvae LD_(50)of 96μg/***:Citrinin(1)is reported from sponge associated Penicillium *** this study and for its strong antibacterial activity against multi-drug resistant human pathogens including cytotoxicity against brine shrimp larvae,which indicated that sponge associated Penicillium *** promising sources of natural bioactive metabolites.

关键词： Penicillium sp. Sponge derived Citrinin Multi-drug resistant Antimicrobial Cytotoxic activity

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A versatile building block:the structures and functions of negative-sense single-stranded RNA virus nucleocapsid proteins

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Protein & Cell 2012年第12期3卷 893-902页

作者： Yuna Sun Yu Guo Zhiyong Lou National Laboratory of Macromolecules Institute of BiophysicsChinese Academy of ScienceBeijing 100101China Laboratory of Structural Biology and MOE Laboratory of Protein Science School of Medicine and Life SciencesTsinghua UniversityBeijing 100084China High-throughput Molecular drug discovery Center Tianjin Joint Academy of Biomedicine and TechnologyTianjin 300457China College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China

Nucleocapsid protein(NPs)of negative-sense single-stranded RNA(-ssRNA)viruses function in different stages of viral replication,transcription,and *** investigations show that-ssRNA viruses that encode NPs preliminarily serve as structural building blocks that encapsidate and protect the viral genomic RNA and mediate the interaction between genomic RNA and RNA-dependent RNA ***,recent structural results have revealed other bio-logical functions of-ssRNA viruses that extend our understanding of the versatile roles of virally encoded NPs.

关键词： -ssRNA virus nucleocapsid protein crystal structure function

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ATN-161 alleviates caerulein-induced pancreatitis

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Journal of Genetics and Genomics 2024年第12期51卷 1447-1458页

作者： Rong-rong Gao Lan-yue Ma Jian-wei Chen Yu-xiang Wang Yu-yan Li Zi-yuan Zhou Zhao-hua Deng Jing Zhong Ya-hai Shu Yang Liu Qi Chen Biomedical Sciences College & Shandong Medicinal Biotechnology Centre Shandong First Medical University & (Shandong Academy of Medical Sciences) NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences) Center for Cell Lineage Atlas Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences University of Chinese Academy of Sciences China-New Zealand Belt and Road Joint Laboratory on biomedicine and Health Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences institutes of Physical Science and Information Technology Anhui University National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital Chinese Academy of Medical Sciences and Peking Union Medical College The Innovation Centre of Ministry of Education for Development and Diseases School of Medicine South China University of Technology Joint School of Life Sciences Guangzhou Medical University

Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality. The mechanistic pathophysiology of pancreatitis is complicated, limiting the discovery of pharmacological intervention methods. Here, we show that the administration of ATN-161, an antagonist of Integrin-a5, significantly mitigates the pathological condition of acute pancreatitis induced by caerulein. We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas. In the caerulein-induced acute pancreatitis model, the newly emergent CK19-positive cells are highly vascularized, with a significant increase in vascular density and endothelial cell number. Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners, suggesting the existence of a ductal-endothelial interface in the pancreas. Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/Integrin-a5 signaling. Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia, pathological angiogenesis, and restores other abnormal defects induced by caerulein. Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.

关键词： ATN-161 Acinar-to-ductal metaplasia Angiogenesis Ductal-endothelial crosstalk Pancreatitis

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drug resistance mechanisms and novel drug targets for tuberculosis therapy

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Journal of Genetics and Genomics 2017年第1期44卷 21-37页

作者： Md Mahmudul Islam H.M. Adnan Hameed Julius Mugweru Chiranjibi Chhotaray Changwei Wang Yaoju Tan Jianxiong Liu Xinjie Li Shouyong Tan Iwao Ojima Wing Wai Yew Eric Nuermberger Gyanu Lamichhane Tianyu Zhang State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou 510530 China University of Chinese Academy of Sciences Beijing 100049 China State Key Laboratory of Respiratory Disease Department of Clinical Laboratory The Guangzhou Chest Hospital Guangzhou 510095 China Institute of Chemical Biology and drug discovery Stony Brook University-State University of New York Stony Brook NY 11794-3400 USA Stanley Ho Centre for Emerging Infectious Diseases The Chinese University of Hong Kong Hong Kong Special Administrative Region China Center for Tuberculosis Research Department of Medicine Johns Hopkins University Baltimore MD 21231-1002 USA

drug-resistant tuberculosis （TB） poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug- resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuber- culosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.

关键词： Tuberculosis Mycobacterium tuberculosis Resistance drug target Mechanism

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A four-protein metabolon assembled by a small peptide protein creates the pentacyclic carbonate ring of aldgamycins

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Acta Pharmaceutica Sinica B 2021年第2期11卷 588-597页

作者： Qiaozhen Wang Xiaolong Tang Ping Dai Chuanxi Wang Weiyang Zhang Guodong Chen Kui Hong Dan Hu Hao Gao Xinsheng Yao Institute of Traditional Chinese Medicine and Natural Product/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New drugs Research College of PharmacyJinan UniversityGuangzhou 510632China Institute of Synthetic Biology Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Key Laboratory of Combinatorial Biosynthesis and drug discovery Ministry of EducationSchool of Pharmaceutical SciencesWuhan UniversityWuhan 430072China

Organic carbonates(OCs)are a class of compounds featured by a carbonyl flanked by two alkoxy/aryloxy *** exist in either linear or cyclic forms,of which the majority encountered in nature adopt a pentacyclic ***,the enzymatic basis for pentacyclic carbonate ring formation remains ***,we reported that a four-protein metabolon(AlmUII-UV)assembled by a small peptide protein(AlmUV)appends a reactive N-hydroxylcarbamoyl moiety to the decarboxylated aldgamycins followed by a non-enzymatic condensation to give the pentacyclic carbonate *** results have documented an unprecedent mechanism for carbonate formation.

关键词： Aldgamycins Biosynthesis N-hydroxylcarbamoyl Organic carbonate Protein complex

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discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1671-1684页

作者： Sameera Senaweera Tiffany C.Edwards Jayakanth Kankanala Yan Wang Rajkumar Lalji Sahani Jiashu Xie Robert J.Geraghty Zhengqiang Wang Center for drug Design College of PharmacyUniversity of MinnesotaMinneapolisMN 55455USA Translational Medicine R&D Center Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated *** developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HCMV in submicromolar *** describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)*** SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–CH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide *** the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity *** preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal *** profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like ***,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

关键词： Human cytomegalovirus N-Benzyl hydroxypyridone carboxamides Structureeactivity relationship Mechanism of action

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The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease

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Protein & Cell 2013年第4期4卷 248-250页

作者： Zhilin Ren Liming Yan Ning Zhang Yu Guo Cheng Yang Zhiyong Lou Zihe Rao College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China Structural Biology Laboratory and MOE Laboratory of Protein Science School of Medicine and Life ScienceTsinghua UniversityBeijing 100084China National Laboratory of Macromolecules Institute of BiophysicsChinese Academy of ScienceBeijing 100101China Emerging Infection Disease Program High-throughput Molecular Drug Discovery CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin 300457China

From the global outbreak of SARS-CoV caused infection disease in 2003,coronaviruses(CoVs)are known to be a great threat to the human ***,a new SARS-like coronavirus,human betacoronavirus 2c EMC/2012(HCoV-EMC),has been identified and the appearance of this new CoV raises concerns that a new spread of CoV may occurs in the *** solving the crystal structure of HCoV-EMC main protease with a wide-spectrum anti-CoV inhibitor N3,we confi rmed that that N3 blocks the function of HCoV-EMC main protease through a similar mechanism to other *** with the good pharmaceutical features,N3 is conceivable to be effective to HCoV-EMC and other CoVs appearing in the *** fi ndings make it convincing that CoVs will not be a threat to human health.

关键词： EMC SARS Together

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Generation of neural progenitor cells from human urine

Generation of neural progenitor cells from human urine

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中国神经科学学会第十届全国学术会议

作者： Guangjin Pan Laboratory Guangzhou institutes of biomedicine and Health Molecular Hefei National

Neural disorders such as spinal cord injury and Parkinson’s diseases have no effective drug treatment and stem cell therapy offer perhaps the only hope for those suffering from these debilitating *** has been intense interest in obtaining human NSCs that may be used to treat these *** developed an efficient process to generate integration-free human NPCs from epithelial-like cells present in human urine *** induced NPCs derived from human urine cells（UiNPCs） could be expanded in vitro and differentiate into subtypes of mature neurons and astrocyte *** transplantation into the brain of newborn rat,the UiNPC survived well and differentiate into astrocytes and neurons in vivo,thus,suitable for potential application in regenerative medicine.

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Characterization of a pangolin SARS-CoV-2-related virus isolate that uses the human ACE2 receptor

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Science China(Life Sciences) 2024年第7期67卷 1502-1513页

作者： Luo-Yuan Xia Xue-Feng Wang Xiao-Ming Cui Yi-Ming Zhang Zhen-Fei Wang En-Tao Li Chang-Fa Fan Ke Song Yuan-Guo Li Run-Ze Ye Fang-Xu Li Dai-Yun Zhu Jie Zhang Zhuang-Zhuang Shi Ming-Zhu Zhang Liang-Jing Li Shi-Jing Shen Song Jin Ya-Wei Zhang Wei-Guang Fu Lin Zhao Wen-Hao Wang Tie-Cheng Wang You-Chun Wang Jia-Fu Jiang Yan-Ling Hu Na Jia Yu-Wei Gao Wu-Chun Cao Institute of EcoHealth School of Public HealthCheeloo College of MedicineShandong UniversityJinan 250012China Changchun Veterinary Research Institute Changchun 130122China State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and EpidemiologyBeijing 100071China Division of Animal Model Research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug ControlBeijing 102629China National institutes for Food and drug Control Beijing 102629China Life Sciences Institute Guangxi Medical UniversityNanning 530020China College of Life Sciences Shandong Normal UniversityJinan 250014China Research Unit of discovery and Tracing of Natural Focus Diseases Chinese Academy of Medical SciencesBeijing 100071China

Various SARS-CoV-2-related coronaviruses have been increasingly identified in pangolins,showing a potential threat to *** we report the infectivity and pathogenicity of the SARS-CoV-2-related virus,PCoV-GX/P2V,which was isolated from a Malayan pangolin(Manis javanica).PCoV-GX/P2V could grow in human hepatoma,colorectal adenocarcinoma cells,and human primary nasal epithelial *** replicated more efficiently in cells expressing human angiotensin-converting enzyme 2(hACE2)as SARS-CoV-2 *** intranasal inoculation to the hACE2-transgenic mice,PCoV-GX/P2V not only replicated in nasal turbinate and lungs,but also caused interstitial pneumonia,characterized by infiltration of mixed inflammatory cells and multifocal alveolar *** population immunity established by SARS-CoV-2 infection and vaccination may not protect people from PCoV-GX/P2V *** findings further verify the hACE2 utility of PCoV-GX/P2V by in vivo experiments using authentic viruses and highlight the importance for intensive surveillance to prevent possible cross-species transmission.

关键词： pangolin SARS-CoV-2-related virus infectivity pathogenicity human cell lines human ACE2 receptor hACE2-transgenic mice

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Neolignans and Norlignans from Insect Medicine Polyphaga plancyi and Their Biological Activities

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Natural Products and Bioprospecting 2021年第1期11卷 51-62页

作者： Hong-Jie Zhu Te Xu Yong-Ming Yan Zheng-Chao Tu Yong-Xian Cheng School of Pharmaceutical Sciences Shenzhen University Health Science CenterShenzhen 518060People’s Republic of China State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of BotanyChinese Academy of SciencesKunming 650201People’s Republic of China International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative drug Development of Chinese Ministry of Education(MOE) College of PharmacyJinan UniversityGuangzhou 510632People’s Republic of China drug discovery Pipeline&Guangdong Provincial Key Laboratory of Biocomputing Guangzhou Institutes of Biomedicine and HealthGuangzhou 510530People’s Republic of China

Ten neolignans or norlignans(1-10)including eight new compounds were isolated from the whole bodies of Polyphaga plancyi *** structures were identified by spectroscopic *** 3,4,8,and 9 are racemates indicated by chiral HPLC *** separation followed by ECD calculations allowed to clarify the absolute configurations of all the *** the new compounds were evaluated for their biological properties toward extracellular matrix in rat renal proximal tubular cells,human cancer cells(K562,A549,and Huh7),EV71,ROCK2,JAK3,DDR1,and coagulation.

关键词： Polyphaga plancyi Insect medicine Lignans Renal protection Anticoagulant activity

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