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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： Chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan kaiming Tang Jian-Piao Cai Kenn ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-Yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye hin Chu Kelvin kai-Wang To Xing-Yi Ge Tao ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China nHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

Down-conversion materials for organic solar cells:Progress,challenges,and perspectives

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Aggregate 2022年第3期3卷 59-79页

作者： Ram Datt Swati Bishnoi harris.n ka hin lee Sandeep Arya Sonal Gupta Vinay Gupta Wing Chung Tsoi Faculty of Science and Engineering Sustainable Product Engineering Centre for Innovative Functional Industrial CoatingsSwansea UniversityBay CampusFabian WaySwansea SA18ENUK Advanced Materials and Metrology Division Council of Scientific And Industrial Research-National Physical LaboratoryDr.K.S.Krishnan MargNew Delhi 110012India Department of Physics University of JammuJammuJammu and Kashmir 180006India Department of Conducting Polymers Institute of Macromolecular ChemistryCzech Academy of SciencesPrague 616206Czech Republic Department of Physics Khalifa University of Science and TechnologyP.O.Box 127788Abu DhabiUnited Arab Emirates

Organic solar cells(OSCs)in terms of power conversion efficiency(PCE)and operational lifetime have made remarkable progress during the last decade by improving the active layer materials and introducing new *** newly developed wide bandgap organic donor and low bandgap acceptor molecules covered the absorption from the visible to the near-infrared *** the incident high energy region(UV)is not in favor of *** absorption causes thermalization losses and photoinduced degradation,which hinders the PCE and lifetime of ***,lanthanide and non-lanthanide-based down-conversion(DC)materials have been introduced,which can effectively convert the high-energy photons(UV)to low-energy photons(visible)and resolve the spectral mismatch losses that limit the absorption of OSCs in high energy incident ***,the DC materials also protect the OSCs from UV-induced *** DC materials were also proposed to cross the Shockley-Queisser efficiency limit of the solar *** this review,the need for DC materials and their processing method for OSCs have been thoroughly ***,the main emphasis has been given to developing lanthanides and non-lanthanides-based DC materials for OSCs,their applications,and their impact on photovoltaic device performance,stability,and future perspectives.

关键词： down-conversion down-shifting lanthanides organic solar cells photostability

Transfusion-transmitted hepatitis E:What we know so far?

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World Journal of Gastroenterology 2022年第1期28卷 47-75页

作者： Carmen ka Man Cheung Sunny Hei Wong Alvin Wing hin Law Man Fai Law Medicine and Therapeutics Prince of Wales HospitalHong Kong 852China Institute of Digestive Disease and Department of Medicine and Therapeutics the Chinese University of Hong KongHong Kong 852China lee Kong Chian School of Medicine Nanyang Technological UniversitySingapore 639798Singapore West Island School Hong Kong 852China

Hepatitis E virus(HEV)is a major cause of viral hepatitis *** is growing concern about transfusion-transmitted HEV(TT-HEV)as an emerging global health *** can potentially result in chronic infection in immunocompromised patients,leading to a higher risk of liver cirrhosis and even *** 0.0013%and 0.281%of asymptomatic blood donors around the world have HEV viremia,and 0.27%to 60.5%have anti-HEV immunoglobulin *** is infectious even at very low blood concentrations of the *** patients who develop persistent hepatitis E infection should have their immunosuppressant regimen reduced;ribavirin may be considered as *** interferon can be considered in those who are refractory or intolerant to ***,a nucleotide analog,showed modest antiviral activity in some clinical studies but sustained viral response was not ***,rescue treatment remains an unmet *** need for HEV screening of all blood donations remains *** screening has been adopted in some countries after consideration of risk and resource *** pathogen reduction methods have also been proposed to reduce the risk of *** studies are needed to define the incidence of transmission through transfusion,their clinical features,outcomes and prognosis.

关键词： Hepatitis E virus Acute and chronic hepatitis Immunosuppression Blood transfusion Transplantation

A Rhizobium bacterium and its population dynamics under different culture conditions of its associated toxic dinoflagellate Gambierdiscus balechii

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Marine Life Science & Technology 2021年第4期3卷 542-551页

作者： Zhen Wu Xiaohong Yang Senjie Lin Wai hin lee Paul K.S.Lam State Key Laboratory of Marine Pollution City University of Hong KongHong KongChina Department of Chemistry City University of Hong KongHong KongChina State Key Laboratory of Marine Environmental Science Xiamen UniversityXiamen 361005China Department of Marine Sciences University of ConnecticutGrotonCT 06340USA Department of Biomedical Sciences City University of Hong KongHong KongChina Shenzhen Key Laboratory for the Sustainable Use of Marine Biodiversity Research Centre for the Oceans and Human HealthCity University of Hong Kong Shenzhen Research InstituteShenzhen 518057China

Rhizobium bacteria are known as symbionts of legumes for developing nodules on plant roots and fixing n2 for the host plants but unknown for associations with ***,we detected,isolated,and characterized a Rhizobium species from the marine toxic dinoflagellate Gambierdiscus *** 16S rRnA gene(rDnA)is 99%identical to that of Rhizobium rosettiformans,and the affiliation is supported by the phylogenetic placement of its cell wall hydrolase-encoding gene(cwh).Using quantitative PCR of 16S rDnA and cwh,we found that the abundance of this bacterium increased during the late exponential growth phase of Gambierdiscus and under nitrogen limitation,suggesting potential physiological interactions between the dinoflagellate and the *** is the first report of dinoflagellate-associated Rhizobium bacterium,and its prevalence and ecological roles in dinoflagellate-Rhizobium relationships remain to be investigated in the future.

关键词： Rhizobium Gambierdiscus 16S rRnA gene Cell wall hydrola Edited by Chengchao Chen

Efficacy of Vaccine Protection Against COVID-19 Virus Infection in Patients with Chronic Liver Diseases

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Journal of Clinical and Translational Hepatology 2023年第3期11卷 718-735页

作者： Carmen ka Man Cheung Kimmy Wan Tung Law Alvin Wing hin Law Man Fai Law Rita Ho Sunny Hei Wong Department of Medicine and Therapeutics Prince of Wales HospitalHong KongChina West Island School Hong KongChina Department of Medicine North District HospitalHong KongChina Institute of Digestive Disease and Department of Medicine and Therapeutics State Key Laboratory of Digestive DiseaseLi Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChinaLee Kong Chian School of MedicineNanyang Technological UniversitySingapore

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality worldwide. Vaccination against coronavirus disease 2019 is a use-ful weapon to combat the virus. Patients with chronic liver diseases (CLDs), including compensated or decompensated liver cirrhosis and noncirrhotic diseases, have a decreased immunologic response to coronavirus disease 2019 vaccines. At the same time, they have increased mortality if infected. Current data show a reduction in mortality when patients with chronic liver diseases are vaccinated. A suboptimal vac-cine response has been observed in liver transplant recipi-ents, especially those receiving immunosuppressive therapy, so an early booster dose is recommended to achieve a better protective effect. Currently, there are no clinical data com-paring the protective efficacy of different vaccines in patients with chronic liver diseases. Patient preference, availability of the vaccine in the country or area, and adverse effect profiles are factors to consider when choosing a vaccine. There have been reports of immune-mediated hepatitis after coronavi-rus disease 2019 vaccination, and clinicians should be aware of that potential side effect. Most patients who developed hepatitis after vaccination responded well to treatment with prednisolone, but an alternative type of vaccine should be considered for subsequent booster doses. Further prospec-tive studies are required to investigate the duration of immu-nity and protection against different viral variants in patients with chronic liver diseases or liver transplant recipients, as well as the effect of heterologous vaccination.

关键词： COVID-19 SARS-CoV-2 Chronic liver disease Liver transplanta-tion Vaccine mRnA.

Mitochondria-targeting self-assembled nanoparticles derived from triphenylphosphonium-conjugated cyanostilbene enable site-specific imaging and anticancer drug delivery

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nano Research 2018年第2期11卷 1082-1098页

作者： ka Young Kim Hanyong Jin Jaehyeon Park Sung Ho Jung Ji Ha lee Hyesong Park Sung Kuk Kim Jeehyeon Bae Jong Hwa Jung Department of Chemistry and Research Institute of natural Sciences Gyeongsang national University Jinju Republic of Korea School of Pharmacy Chung-Ang University Seoul Republic of Korea

Subcellular organelle-specific nanoparticles for simultaneous tumor targeting, imaging, and drug delivery are of enormous interest in cancer therapy. Herein, we report a selective mitochondria-targeting probe 1, which was synthesized by incorporating a triphenyl phosphine with a cyanostilbene and a long alkyl chain moiety. Probe 1 was found to display fluorescence via aggregation-induced emission （AIE）. The low molecular-weight cyanostilbene-based probe 1, with and without an anticancer drug, formed a narrow homogeneous nanorod with ca. 110 nm of length or nanopartides with ca. 20 nm diameter in aqueous media. The self-assembled cyanostilbene nanoparticles （n1） selectively accumulated in the mitochondria of cancer cells and emitted fluorescence. n1 was also able to deliver an anticancer drug, doxorubicin （DOX）, to the mitochondria with high efficiency. More importantl~ n1 exhibited highly selective cytotoxicity for cancer cells over normal cells. The great potential applications of this self-assembled nanoparticle to biological systems result from its ability to aggregate in the mitochondria. This aggregation led to a significant increase in the generation of intraceUular reactive oxygen species and to a decrease in the mitochondrial membrane potential in cancer cells. Furthermore, tumor tissue uptake experiments in mice proposed that the self-assembled n1 had the ability to internalize and deliver the anticancer drug into tumor tissues effectively. Moreover, both n1 and nl-encapsulated doxorubicin （n1-DOX） effectively suppressed tumor growth in a xenograft model in vivo. Taken together, our findings indicate that applications of n1 as a mitochondrial targeting probe, drug delivery platform, and chemotherapeutic agent provide a unique strategy for potential image-guided therapy as well as a site-specific delivery system to cancer cells.

关键词： aggregation-inducedemission,chemotherap3 drug deliver3 mitochondria-targeting,fluorescence imaging

A cross-sectional study on compliance with topical glaucoma medication and its associated socioeconomic burden for a Chinese population

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International Journal of Ophthalmology(English edition) 2017年第2期10卷 293-299页

作者： Man-hin Lui Jason Chun Ho Lam Yi lee Kwong Tak Siu Wong Pak Long Cheung Sherri Shun Yan Lai Pak Lun Yuen Wai Yiu Lam Ho Yan Chan Yiu Fai Wong Jimmy Shiu Ming Lai Kendrick Co Shih Li ka Shing Faculty of Medicine the University of Hong KongPokfulamHong KongChina Department of Ophthalmology Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHongKongChina Department of Ophthalmology Queen Mary HospitalPokfulamHong KongChina

AIM： To estimate the overall drug compliance for local Chinese glaucoma patients on long-term topical ***： This was a retrospective cross-sectional ***-seven primary glaucoma patients from the subspecialty clinic of a publicly-funded tertiary care hospital in Hong Kong completed a questionnaire on compliance with topical glaucoma medication,attitude towards glaucoma and therapy and vision related quality of *** was defined as reporting missing more than or equal to 10% of the prescribed topical glaucoma medication during the 2wk immediately prior to the *** between noncompliance and demographics,attitude,disease and treatment status was *** was estimated with quality of life and direct medical cost involved with *** logistic regression on noncompliance was performed on selected ***： Compliance was calculated as 75%（95% CI： 64%-87%） among 57 subjects（mean age 69 y,female 51%）.no statistical significant relationship was established between noncompliance and any single factors or ***（P=0.048） and forgetfulness（P=0.064） were found to be marginally significant predictive factors on noncompliance in multivariable logistic *** might be related（P=0.130） to poorer self-rated vision-associated quality of *** societal cost of noncompliance was estimated to be over 2510 life-years and US$ 3.7 million ***： The compliance of Chinese glaucoma patients in Hong Kong is comparable to other parts in the world,and carries detrimental impacts on individual and societal *** and forgetfulness are two possible independent predictors for noncompliance.

关键词： glaucoma eye drop compliance quality of life

Enhanced replication of SARS-CoV-2 Omicron BA.2 in human forebrain and midbrain organoids

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Signal Transduction and Targeted Therapy 2022年第12期7卷 4257-4260页

作者： Yuxin Hou Chang Li Chaemin Yoon On Wah Leung Sikun You Xiaoming Cui Jasper Fuk-Woo Chan Duanqing Pei Hoi Hung Cheung hin Chu State Key Laboratory of Emerging Infectious Diseases Department of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong Kongand Centre for VirologyVaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong Special Administrative RegionChina State Key Laboratory of Emerging Infectious Diseases Department of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong Kong Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong Special Administrative RegionChina

Dear Editor,Coronavirus Disease 2019(COVID-19)is associated with a variety of neurological complications,including encephalopathy,encephalitis,dementia,and others.1 The pathogenic mechanism of these neurological manifestations remains incompletely understood but may be due to factors such as coagulation problem,immune-mediated response,or direct viral invasion into the central nervous system(CnS).2 We and others previously reported that ancestral SARS-CoV-2 could infect and replicate in human brain organoids.3,4 More recently,SARS-CoV-2 Omicron BA.1 emerged in late 2021 and demonstrated altered virological features including increased immunoevasion and attenuated pathogenicity comparing to SARS-CoV-2 wildtype(WT)and previous variants.5 However,the neuroinvasiveness of Omicron sublineages remain ***,we investigated the neuroinvasion and neurotoxicity of Omicron BA.1 and BA.2,and compared the findings with those of SARS-CoV-2 WT and Delta in human forebrain and midbrain *** results demonstrated that BA.2 replicated more efficiently while triggered lower levels of type I interferon response than that of SARS-CoV-2 WT,Delta,and BA.1 in both human forebrain and midbrain *** addition,BA.2 triggered substantially higher levels of apoptosis in the infected human forebrain and midbrain ***,these findings suggest that BA.2 may be different from SARS-CoV-2 WT and previous variants in its capacity in targeting and causing diseases in the human brain.

关键词： invasion finding incomplete

Determinants for asthma control, quality of life and use of complementary and alternative medicine in asthmatic pediatric patients in four cities

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World Journal of Pediatrics 2018年第5期14卷 482-491页

作者： kam Lun Hon Yan Min Bao kate C.Chan Kin Wai Chau Rong-Shan Chen Kun Tat Gary Cheok Wa Keung Chiu Li Deng Chun-Hui He Kin Mui Ieong Jeng Sum C.Kung Ping Lam Shu Yan David Lam Qun Ui lee So Lun lee Ting Fan Leung Theresa n.H.Leung Lei Shi ka ka Siu Wei-Ping Tan Maggie Haitian Wang Tak Wai Wong Bao-Jing Wu Ada Y.F.Yip Yue-Jie Zheng Daniel K.ng Department of Pediatrics The Chinese University of Hong Kong 6/F Prince of Wales HospitalRoom 84042ShatinN.THong Kong SARChina Department ofR espiratory Diseases Shenzhen Children’s HospitalShenzhen 518026China Hong Kong Society of P ediatric Respirology and Aller gy Hong K ong S ARChina Pediatric Respiratory andSleep Disorders Center Room 1315DArgyle Centre Phase 1688 Nathan RoadMongkokKowloonHong K ong S ARChina Department of R espiration Guangzhou Women and Children’s Medical CenterGuangzhou 510623China Department of P ediatrics Kiang Wu HospitalMacaoChina Department of P ediatrics and A dolescent Medicine United Christian Hospital130Hip Wo StreetKwun TongHong K ong S ARChina Department of P ediatrics Central Hospital Conde S.JanuarioMacaoChina Department of P ediatrics and A dolescent Medicine Caritas Medical Center111Wing Hong StreetSham Shui PoHong K ong S ARChina Department of P ediatrics and A dolescent Medicine Tuen Mun Hospital23 Tsing Chung Koon RoadTuen MunNewT erritoriesHongK ongS ARChina Department of P ediatrics and A dolescent Medicine Princess Margaret Hospital2-10 Princess Margaret Hospital RoadLai Chi KokKowloonHong K ong S ARChina Department of P ediatrics and A dolescent Medicine Queen Mary Hospital102Pokfulam RoadHong K ong S ARChina Department of P ediatrics and A dolescent Medicine The University of Hong KongHong K ong S ARChina Department of P ediatrics and A dolescent Medicine Pamela Youde Nethersole Eastern Hospital3Lok Man RoadChaiwanHong K ong S ARChina Department of P ediatrics The University of Hong Kong-Shenzhen Hospital1Haiyuan 1st RoadFutianShenzhenChina Department of P ediatrics and A dolescent Medicine Kwong Wah Hospital25 Waterloo RoadKLN Hong K ong S ARChina Department of P ediatrics Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China JC School of Public Health and Primary Care Faculty of MedicineThe Chinese University of Hong KongHong K ong S ARChina Department of P ediatrics and A dolescen

Background Asthma is a significant chronic health problem worldwide. Management aims at disease control by reducing functional impairment and exacerbations and improving quality of life (QoL). We report a multi-center study to survey asthma control and QoL in four cities in the Pearl River Delta. Methods The conjoint survey involved ten Hong Kong pediatric hospitals/units, two Shenzhen hospitals, two Macao hos-pitals, and two Guangzhou hospitals on asthma control (using Asthma Control Test) and QoL (Pediatric Allergic Disease Quality of Life Questionnaire, PADQLQ). Acceptability of a treatment is graded as very good/good/fair/poor. Results Good asthma control was only reported in 80% subjects in Hong Kong, but higher in sister cities (85–94%, Phinitis, 'incense burning', and 'smoker in family' were prevalent among the four cities. Logistic regres-sion showed better control of asthma was associated with better PADQLQ (B=?0.029, P nchodilator (B=?1.488, P = 0.025), negatively with 'smoker in family' (B=?0.83, P = 0.015) and various PADQLQ domains. Conversely, worse PADQLQ was associated with allergic rhinitis severity (B=4.77, P ntrol of asthma (B=7.56, P ncreased frequency of traditional Chinese medicine use (B=1.7, P ncreased fre-quency of bronchodilator usage (B=1.05, P n family' (B=4.05, P nd incense burning at home (B=3.9, P nclusions There are some clinical and cultural differences among the four southern Chinese cities within the Guangdong province. This study identifies potentially modifiable environmental and treatment factors associated with poor asthma control and QoL for health-care interventions. Having a smoker in the family is independently associated with poor asthma control and QoL.

关键词： Asthma Complementary and alternative medicine Control Inhaled bronchodilator Inhaled corticosteroid Pediatric Allergic Disease Quality of Life Questionnaire Smoking Traditional Chinese medicine