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The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2039-2055页

作者： Kan Xing Wu Thinesshwary Yogarajah Marcus Wing Choy Loe Parveen Kaur Regina Ching Hua Lee Chee Keng Mok Yi Hao Wong Patchara Phuektes Li Sze Yeo Vincent T.K.Chow Yong Wah Tan Justin Jang Hann Chu Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University Health SystemNational University of SingaporeSingapore 117597Singapore Department of Pathobiology Faculty of Veterinary MedicineKhonkaen UniversityKhonkaen 40002Thailand Infectious Disease Programme Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore Institute of Molecular and Cell Biology Agency for ScienceTechnology and Research(A∗STAR)Singapore 138648Singapore Lee Kong Chian School of Medicine Nanyang Technological UniversitySingapore 308232Singapore NUSMed Biosafety Level 3 Core Facility Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117599Singapore

Positive-sense RNA viruses modify intracellular calcium stores,endoplasmic reticulum and Golgi apparatus(Golgi)to generate membranous replication organelles known as viral *** factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in ***,we identified the vital role of a broadspectrum antiviral,peruvoside in limiting the formation of viral ***,we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1(GBF1)phosphorylation and Golgi vesiculation by peruvoside *** ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories *** investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337(T1337).We also showed 100%of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in *** findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside,host-directed antivirals for positive-sense RNA virus-mediated disease,in the interim where no vaccine is available.

关键词： Positive-sense RNA viruses Peruvoside Antiviral CDKI signaling Viral factories Calcium efflux broad-spectrum Golgi apparatus

Membrane-targeting amphiphilic AIE photosensitizer for broad-spectrum bacteria imaging and photodynamic killing of bacteria

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Chinese Chemical Letters 2023年第9期34卷 183-187页

作者： Haining Zhang Chaojun He Limin Shen Wenjun Tao Jianhui Zhu Jinzhao Song Ziyong Li Jun Yin Luoyang Key Laboratory of Organic Functional Molecules College of Food and DrugLuoyang Normal UniversityLuoyang 471934China Key Laboratory of Pesticide and Chemical Biology Ministry of EducationHubei International Scientific and Technological Cooperation Base of Pesticide and Green SynthesisInternational Joint Research Center for Intelligent Biosensing Technology and HealthCollege of ChemistryCentral China Normal UniversityWuhan 430079China

An amphiphilic AIE photosensitizer has been successfully developed,which allows for easily inserting into the bacterial *** experiments with phospholipid preliminary demonstrates its membrane *** expected,it is proved to possess a broad-spectrum bacterial staining performance and photodynamic antibacterial activity toward *** and ***.

关键词： Photodynamic therapy Aggregation-induced emission Photosensitizer Membrane-targeting Singlet oxygen broad-spectrum Bacteria imaging

Increasing Incidence of Extended-spectrum Beta-Lactamase-Producing Enterobacteriaceae (ESBL) and the Relation to Consumption of broad-spectrum Antimicrobial Agents 2003-2011 in a Large Area of Copenhagen, Denmark

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Open Journal of Medical Microbiology 2015年第1期5卷 28-42页

作者： Lene Nielsen Anne Kjerulf Magnus Arpi Department of Clinical Microbiology Copenhagen University Hospital Herlev Denmark Department of Microbiology and Infection Control at Statens Serum Institut Copenhagen Denmark

Purpose: To investigate 1) the development in the incidence of ESBL-producing bacteria in hospitals and primary health care, 2) the contribution of primary health care to the incidence of ESBL-producing bacteria, and 3) the development in resistance patterns for all Escherichia coli and Klebsiella pneumoniae isolates in relation to antimicrobial consumption in hospitals and primary health care. Methods: ESBL-data were retrospectively collected from bacterial isolates from all specimens received at the Department of Clinical Microbiology from 2003 to 2011 together with the corresponding patient data. ESBL-production was detected in isolates from 1067 of 59,373 patients (1.8%) with an E. coli infection and in 263 of 8660 patients (3.0%) with a K. pneumoniae infection. Results: From 2003 to 2009, an increase in patients with an ESBL-producing isolate occurred in both hospitals and primary health care at the same time as an increased consumption of broad-spectrum antimicrobial agents was seen. Interventions to reduce prescription of cephalosporins and ciprofloxacin at the hospitals from 2010 resulted in a remarkable decrease in patients with ESBL-producing K. pneumoniae whereas a continuing increase was seen in patients with ESBL-producing E. coli both at hospitals and in primary health care. The proportion of patients with community-acquired ESBL-producing E. coli was stable with an increase of only 1.4% from 2007 to 2011. Conclusions: Reduction in prescription of broad-spectrum antimicrobial agents at the hospital level had an important impact on the incidence of ESBL-producing K. pneumoniae, but not on ESBL-producing E. coli.

关键词： Incidence of ESBL-Producing E. coli and K. pneumoniae Hospital Care Primary Health Care Antimicrobial Consumption broad-spectrum Antimicrobial Agents

Effectiveness of a broad-spectrum Sunscreen in the Prevention of Melasma in Asian Pregnant Women

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Journal of Cosmetics, Dermatological Sciences and Applications 2013年第3期3卷 4-7页

作者： Sophie Seité Seok Beom Park La Roche-Posay Pharmaceutical Laboratories Asnières France Leaders Clinic Seoul Korea

Chloasma, or melasma, is a commonly acquired pigmentary disorder among Asian women. It may be considered as a physiological change during pregnancy. The incidence in Asian women is higher than that in other ethnic groups but further epidemiologic data are needed. There are very few studies related to the benefits of sunscreens to prevent this dermatosis. The aim of this study was to assess the effectiveness of a broad-spectrum sunscreen in the prevention of melasma in Korean pregnant women. We tested the effectiveness and tolerance of a sunscreen product (SPF 50+, UVA-PF 30) during a 12-month clinical trial including 220 Korean parturients with skin type III and IV. 217 women completed the study. Only 3 (1%) of the study population developed melasma, which was mild (MASI grade between 1.2 and 2.7). In addition, the clinical effectiveness of the evaluated sunscreen was judged “good to excellent” by the majority of study participants and by the research dermatologists. The “excellent” tolerance of the sunscreen under evaluation was confirmed “good” to “excellent” in 95% and 97% of cases. This study clearly demonstrates that this broad-spectrum sunscreen is well tolerated and effective in the prevention of melasma in Korean pregnant women. Although treatment remains elusive, prevention is possible.

关键词： broad-spectrum Sunscreen Chloasma Melasma Pregnancy Photoprotection SPF UVA-PF

Nanobodies with cross-neutralizing activity provide prominent therapeutic efficacy in mild and severe COVID-19 rodent models

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Virologica Sinica 2023年第5期38卷 787-800页

作者： Qiuxue Han Shen Wang Zhenshan Wang Cheng Zhang Xinyue Wang Na FengTiecheng Wang Yongkun Zhao Hang Chi Feihu Yan Xianzhu Xia Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100021China Changchun Veterinary Research Institute Chinese Academy of Agricultural SciencesChangchun132122China Jiangsu Co-innovation Centre for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou225009China

The weakened protective efficacy of COVID-19 vaccines and antibodies caused by SARS-CoV-2 variants presents a global health emergency,which underscores the urgent need for universal therapeutic antibody intervention for clinical ***,we screened three alpacas-derived nanobodies(Nbs)with neutralizing activity from twenty RBD-specific *** three Nbs were fused with the Fc domain of human IgG,namely aVHH-11-Fc,aVHH-13-Fc and aVHH-14-Fc,which could specifically bind RBD protein and competitively inhibit the binding of ACE2 receptor to *** effectively neutralized SARS-CoV-2 pseudoviruses D614G,Alpha,Beta,Gamma,Delta,and Omicron sub-lineages BA.1,BA.2,BA.4,and BA.5 and authentic SARS-CoV-2 prototype,Delta,and Omicron BA.1,BA.2 *** mice-adapted COVID-19 severe model,intranasal administration of aVHH-11-Fc,aVHH-13-Fc and aVHH-14-Fc effectively protected mice from lethal challenges and reduced viral loads in both the upper and lower respiratory *** the COVID-19 mild model,aVHH-13-Fc,which represents the optimal neutralizing activity among the above three Nbs,effectively protected hamsters from the challenge of SARS-CoV-2 prototype,Delta,Omicron BA.1 and BA.2 by significantly reducing viral replication and pathological alterations in the *** structural modeling of aVHH-13 and RBD,aVHH-13 binds to the receptor-binding motif region of RBD and interacts with some highly conserved *** together,our study illustrated that alpaca-derived Nbs offered a therapeutic countermeasure against SARS-CoV-2,including those Delta and Omicron variants which have evolved into global pandemic strains.

关键词： COVID-19 SARS-CoV-2 Nanobody broad-spectrum Therapeutic Rodent models

Decontamination of Chemical Warfare Agents by Novel Oximated Acrylate Copolymer

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Chemical Research in Chinese Universities 2019年第6期35卷 1095-1104页

作者： WEN Xianfang YE Lin CHEN Likun KONG Lingce YUAN Ling XI Hailing ZHONG Jinyi State Key Laboratory of NBC Protection for Civilian Beijing 102205P.R.China School of Material Science and Engineering Beijing Institute of TechnologyBeijing 100081P.R.China Research Institute of Chemical Defense Beijing 102205P.R.China

A novel acrylate copolymer,polymethylacrylate-β-(bromoacetyl ethyl)ester-co-N,N-dimethylacrylamide[P(MABE-co-DMAA)]was synthesized by the copolymerization of N,N-dimethylacrylamide and methylacrylate-β-(bromoacetyl ethyl)***,the copolymer was oximated by 4-pyridinium aldoxime(4-PAM),and was abbreviated as PAM-P(MABE-co-DMAA).A maximum oxime conversion of 53.7%was *** as-prepared oximated copolymer PAM-P(MABE-co-DMAA)effectively decontaminated chemical warfare agents(CWAs)including methylphosphonofluoridate(sarin or GB),S-2-(diisopropylamino)ethyl O-ethyl methylphosphonothioate(VX),and 2,2′-dichloroethyl sulfide(sulfur mustard,or HD).The detoxification rates were 90.6%for GB,85.7%for VX,and 90.5%for *** analysis,high performance liquid chromatography-mass spectrometry(HPLC/MS)and gas chromatography-mass spectrometry(GC/MS)were used to identify the decontamination products,and the decontamination mechanism was concluded to be a combination of nucleophilic substitution and a second order Beckmann ***,the active decontamination materials,such as decontamination cloths and covers could be made from the oximated copolymer by virtue of its processability,as well as its strong ability to degrade CWA.

关键词： Oximated copolymer Chemical warfare agent Decontamination material broad-spectrum decontaminating Detoxification rate

Glyphosate-based herbicide: a risk factor for demyelinating conditions of the peripheral nervous system?

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Neural Regeneration Research 2019年第12期14卷 2079-2080页

作者： Fabian Szepanowski Christoph Kleinschnitz Mark Stettner Department of Neurology University Medicine Essen University Duisburg-Essen

Glyphosate is a broad-spectrum herbicide originally introduced to the market in 1974 by the agrochemical company Monsanto. More than 40 years down the line, glyphosate has become one of the most economically meaningful herbicides, with a global use of more than 1.8 million pounds in 2014 (Benbrook, 2016). In non resistant plants, glyphosate is widely believed to exert its herbicidal effect via inhibition of the 5-enolpyruvylshikimate-3-phosphate synthase, an enzyme of the shikimate pathway required for the biosynthesis of aromatic amino acids in plants and most microorganisms such as fungi, bacteria and some protozoans.

关键词： Glyphosate-based herbicide broad-spectrum herbicide economically meaningful herbicides

Jun12682,a potent SARS-CoV-2 papain-like protease inhibitor with exceptional antiviral efficacy in mice

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4189-4192页

作者： Mianling Yang Meehyein Kim Peng Zhan Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJi’nan 250012China Infectious Diseases Therapeutic Research Center Korea Research Institute of Chemical Technology(KRICT)Daejeon 34114Republic of Korea

Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-2 papain-like protease(PL^(pro)).The study demonstrated nanomolar PL^(pro) inhibitory potency with K_(i) values ranging from 13.2 to 88.2 nmol/*** employing a structure-based drug design strategy,the researchers discovered an exceptionally promising compound,named Jun12682,that effectively targets both the newly discovered ubiquitin Val70(Val70^(Ub))-binding site and the known blocking loop(BL2)groove near the S4 subsite of PL^(pro).Furthermore,studies on the mechanism of action revealed that Jun12682 inhibits the deubiquitinating and deISGylating activities of PLpro,which are crucial for antagonizing the host’s innate immune response upon viral *** biology studies confirmed the“two-pronged”binding mode of Jun12682,aligning perfectly with their drug design ***,Jun12682 exhibited potent antiviral activity against SARS-CoV-2 and its variants,including nirmatrelvir-resistant mutants,in Caco-2 cells(EC_(50):0.44-2.02 μmol/L).It is noteworthy that its oral administration significantly improved survival rates and alleviated both lung virus loads and histopathological lesions in a lethal SARS-CoV-2 mouse *** conclusion。

关键词： SARS-CoV-2 Papain-like protease broad-spectrum Anti-drug resistance Drug candidate

Lycorine derivative effectively inhibits the replication of coronaviruses both in vitro and in vivo

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hLife 2024年第2期2卷 75-87页

作者： Liang Shen Jianzhong Zhao Ying Xia Junjie Lu Jiali Sun Jian Tang Hui Xing Lijuan Yin Yang Yang Chunhua Wang Department of Clinical Laboratory Xiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceHubeiChina Shenzhen Key Laboratory of Pathogen and Immunity National Clinical Research Center for Infectious DiseaseState Key Discipline of Infectious DiseaseShenzhen Third People’s HospitalSecond Hospital Affiliated to Southern University of Science and TechnologyGuangdongChina Department of Clinical Laboratory Xiangyang No.1 People’s HospitalHubei University of MedicineHubeiChina State Key Laboratory of Food Nutrition and Safety Key Laboratory of Industrial MicrobiologyMinistry of EducationTianjin Key Laboratory of Industry MicrobiologyNational and Local United Engineering Lab of Metabolic Control Fermentation TechnologyChina International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal ChemistryCollege of BiotechnologyTianjin University of Science&TechnologyTianjinChina

The established and ongoing prevalence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and seasonal human coronaviruses(HCoV)like HCoV-OC43,HCoV-NL63,and HCoV-229E,pose a continuous threat to public ***,it is urgently needed to explore antiviral drugs with broad-spectrum anti-coronavirus *** previous studies have revealed that lycorine is a potent broad-spectrum anti-coronavirus drug,a natural alkaloid extracted from Amaryllidaceae with various pharmacological and microbiological ***,it is unsafe to directly use lycorine as a clinical antiviral drug due to the cytotoxicity and induction of cell *** this study,a series of lycorine derivatives were designed and *** of them,named Ly-8,was found to effectively inhibit the replication of different coronavirus strains in vitro,including ***,Ly-8 was also shown to effectively inhibit HCoVOC43 replication in the central nervous system,and provide effective protection against HCoV-OC43 infection in mice with low drug ***,Ly-8-resistant mutants were not observed during the 30 times sequential passages in cell ***,these findings suggest that Ly-8 may be a potential candidate drug for the future development of broad-spectrum anti-coronavirus drugs.

关键词： broad-spectrum antiviral drug lycorine derivative Ly-8