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Targeting papain-like protease for broad-spectrum coronavirus inhibition

Protein & Cell 2022年第12期13卷 940-953页

作者： Shuofeng Yuan Xiaopan Gao Kaiming Tang Jian-Piao Cai Menglong Hu Peng Luo Lei Wen Zi-Wei Ye Cuiting Luo Jessica Oi-Ling Tsang chris chun-yiu chan Yaoqiang Huang Jianli Cao Ronghui Liang Zhenzhi Qin Bo Qin Feifei Yin Hin Chu Dong-Yan Jin Ren Sun Jasper Fuk-Woo chan Sheng Cui Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Microbiology Li Ka ShingFaculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina Department of Molecular and Medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCAUSA Key Laboratory of Tropical Translational Medicine of Ministry of Education Hainan Medical UniversityHaikou 571199China Academician Workstation of Hainan Province Hainan Medical UniversityHaikou 571199China Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases The University of Hong KongPokfulamHong Kong Special Administrative RegionChina Guangzhou Laboratory Guangzhou 510320China Department of Clinical Microbiology and Infection Control The University of Hong Kong-Shenzhen HospitalShenzhen 518053China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral *** the multi-functional papain-like protease(PLpro)domain of the viral nsp3 holds ***,none of the known coronavirus PLpro inhibitors has been shown to be in vivo ***,we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity,including against the Sarbecoviruses(SARSCoV-1 and SARS-CoV-2),Merbecovirus(MERS-CoV),as well as the Alphacoronavirus(hCoV-229E and hCoVOC43).Importantly,F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice.F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage,as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase *** the significant difference of substrate recognition,mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue,whereas an allosteric inhibitor of MERSPLpro interacting with its 271E *** proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anticoronavirus *** orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.

关键词： protease inhibitor coronavirus Nsp3 antiviral

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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

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Single-pilot operations in commercial flight:Effects on neural activity and visual behaviour under abnormalities and emergencies

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Chinese Journal of Aeronautics 2024年第8期37卷 277-292页

作者： Qinbiao LI chun-Hsien CHEN Kam K.H.NG Xin YUAN Cho Yin yiu Human Factors and Ergonomics Laboratory Department of Aeronautical and Aviation EngineeringThe Hong Kong Polytechnic UniversityHong Kong Special Administrative Region 100872China School of Mechanical&Aerospace Engineering Nanyang Technological UniversitySingapore 639798Singapore

With cutting-edge technologies and considering airline human-resource-saving,a single pilot in commercial jets could be technically *** changes in captains’natural behaviours are initially required to comprehend the specific safe human performance envelope for safeguarding single-pilot flight,particularly in high-risk *** paper investigates how captains’performance transforms for fixing emergencies when operating from Dual-Pilot Operations(DPO)to Single-Pilot Operations(SPO)through a physiological-based *** pilots flew an emergency-included flight with/without first officers’*** neural activities and scanning behaviours were recorded using a 32-channel Electroencephalogram(EEG)and glasses-based eye tracker,with the observation and post-experiment questionnaires to evaluate the flight operations and pilots’*** alone,there was a significantly increased cortical activity in h and b waves over the frontal,parietal,and temporal lobes during the more complicated emergencies,and pilots focused less on the primary flight display while spending significantly more time scanning the other *** physiological fluctuating patterns associated with risky operations in SPO were highlighted by cross-correlating multimodal *** experimental-based noteworthy insights may wish to inform commercial SPO measures to lessen the persistent physiological fluctuation,assisting airlines in creating SPO-oriented intelligent flight systems to give captains adequate support for assuring safer air transportation.

关键词： Aviation engineering Single pilot operations Behaviour changes Eye tracker Electroencephalogram

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Development of Dual Phosphorescent Materials Based on Multiple Stimuli-Responsive Ir(Ⅲ)Acyclic Carbene Complexes

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CCS Chemistry 2022年第7期4卷 2354-2368页

作者： Jingqi Han Yuen-Kiu chun Shing-Lun chan Shun-Cheung Cheng Shek-Man yiu Chi-Chiu Ko Department of Chemistry City University of Hong KongKowloonHong Kong 999077

A new series of Ir(Ⅲ)carbene complexes with luminescent mechanochromism derived from trans-cis isomerization has been *** the introduction of π-conjugating groups into the acyclic carbene ligand,the mechanochromic trans-and cisconfigurations can be readily interconverted,leading to dual emissive properties in the solid ***,the solid-or film-forming solvent system can control the dual emission and mechanoresponsive properties in the solid *** potential uses of a single emissive complex to develop multicolor emissive and multiple stimuli-responsive films have been studied.

关键词： luminescent mechanochromism iridium(Ⅲ)cyclometallates luminescent vapochromism dual emission

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Rare case of intussusception in an adult with acute myeloid leukemia

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World Journal of Gastroenterology 2015年第2期21卷 688-693页

作者： Man Fai Law Cheuk Kei Wong chun Yin Pang Hay Nun chan Ho Kei Lai chung Yin Ha Celia Ng yiu Ming Yeung Sze Fai Yip Department of Medicine Tuen Mun Hospital Department of Medicine and Therapeutics Prince of Wales Hospital Department of Radiology Kwong Wah Hospital Department of Pathology Tuen Mun Hospital

Intussusception is rarely reported in adult patients with acute leukemia. We report a case of intussusception in a 29-year-old woman with acute myeloid leukemia(AML). She developed right lower quadrant pain, fever, and vomiting on day 16 of induction *** examination showed tenderness and guarding at the right lower quadrant of the abdomen. Abdominal computed tomography(CT) showed distension of the cecum and ascending colon, which were filled with loops of small bowel, and herniation of the ileocecal valve into the cecum. We proceeded to laparotomy and revealed ileocecal intussusception with the ileocecal valve as the leading point. The terminal ileum was thickened and invaginated into the cecum, which showed gangrenous changes. Right hemicolectomy was performed and microscopic examination of the colonic tissue showed infiltration of leukemic cells. The patient recovered after the operation and was subsequently able to continue treatment for AML. This case demonstrates that the diagnosis of intussusception is difficult because the presenting symptoms can be non-specific, but abdominal CT can be informative for preoperative diagnosis. Resection of the involved bowel is recommended when malignancy is suspected or confirmed. Intussusception should be considered in any leukemia patients presenting with acute abdomen. A high index of clinical suspicion is important for early diagnosis.

关键词： Intussusception Acute leukemia Abdominal pain Colo

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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

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Intra-cranial metastasis of gastrointestinal stromal tumor

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Chinese Medical Journal 2011年第21期000卷 3595-3597页

作者： WONG chun-sing CHU yiu-ching Department of Diagnostic Radiology Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong China Department of Radiology Kwong Wah Hospital Hong Kong China

With the evolution of immunochemical staining techniques and better imaging modalities with better image resolution and whole body coverage, gastrointestinal stromal tumor （GIST）, the most common mesenchymal tumor of the gastrointestinal tract, is often encountered in clinical practice. Metastasis is common with malignant GIST and can be found in up to 50% of patients at presentation. Liver and peritoneum are the two most common sites of metastasis and accounted for 95% of cases. Lymphatics, bone and lung metastasis are rare. Malignant GIST with intracranial metastasis is even rarer, with only a few cases reported in the literature, and most of these had earlier metastasis elsewhere. Radiological features for GISTs are not specific but it does contribute to confirming early and accurate diagnosis of malignant GISTs by judging the tumor size, enhancement pattern and the invasion of adjacent structures. We report a case of a 26-year-old male with metastatic GIST to the liver and subsequently to the brain and skull vault. This is the first case reported in our locality and he is the youngest patient reported with this disease entity. The clinical progress, radiological features and the role of imaging will be discussed further in this paper. The radiological and clinical features of the primary tumor will specifically be addressed. The purpose of this paper is to enrich the current database of this rare disease entity and to alert both radiologists and clinicians about the imaging features of GIST with intracranial metastasis.

关键词： gastrointestinal stromal tumor imatinib intracranial metastasis

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Virtual reality based multiple life skill training for intellectual disability:A multicenter randomized controlled trial

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Engineered Regeneration 2022年第2期3卷 121-130页

作者： James chung-Wai Cheung Ming Ni Andy yiu-Chau Tam Tim Tin-chun chan Alyssa Ka-Yan Cheung Ocean Yu-Hong Tsang Chi-Bun Yip Wing-Kai Lam Duo Wai-Chi Wong Department of Biomedical Engineering Faculty of EngineeringThe Hong Kong Polytechnic UniversityHong Kong 999077China Research Institute for Smart Ageing The Hong Kong Polytechnic UniversityHong Kong 999077China Jockey Club Smart Ageing Hub Department of Biomedical EngineeringFaculty of EngineeringThe Hong Kong Polytechnic UniversityHong Kong 999077China Department of Orthopaedics Pudong New Area People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 201299China Social Service Department Yan Chai HospitalHong Kong 999077China C2 Innovations and Research Limited Hong Kong 999077China Department of Kinesiology Shenyang Sport UniversityShenyang 110102China Sports Information and External Affairs Centre Hong Kong Sports InstituteHong Kong 999077China

Life skill-based training is essential for intellectual disabled individuals to regain autonomy and social *** reality(VR)could deliver a nascent application that is more engaging and *** objective of this study was to evaluate the training effects of the VR-based multiple life skill training program on life skill perfor-mance,self-efficacy,memory,cognitive and behavioral functions via a multicenter randomized controlled trial.A total of 145 intellectual disabled participants were recruited for a randomized controlled trial with three in-tervention arms:VR(n=42);traditional(n=53);and control(n=50).The life skill tasks for the interventions included 1)grocery shopping,2)cooking,and 3)kitchen *** measures were performance scores for the three tasks,self-efficacy scale,digit span score,and Frontal Assessment Battery score,graded by blinded ***-after effects of each group were evaluated using separated Wilcoxon Signed-rank *** sig-nificantly improved cooking,cleaning performance,and memory span,while traditional training significantly improved shopping,cooking,and cleaning *** generalized estimating equation evaluated effects between groups adjusted for age,gender and intelligence quotient(IQ).VR had significantly larger improvement effects in cooking and cleaning than the control group and memory span compared to traditional training and controls *** appeared to be a significant confounder on the training *** work may consider developing artificial intelligence to customize programs depending on IQ level.

关键词： Mental retardation Intellectual development X-reality Immersive rehabilitation Metaverse

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New Sesquiterpene Glycosides from Culture Hairy Roots of Catharanthus roseus

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Chinese Journal of Chemistry 2007年第11期25卷 1695-1699页

作者： chunG, ILL-Min ALl, Mohd chun, Se-Chul LEE, Sun-Joo SAN, Ka-yiu chrisTIE, A. M. Peebles AHMAD, Ateeque Department of Applied Life Science Konkuk University Seoul 143-701 South Korea Faculty of Pharmacy Hamdard University New Delhi 110062 India Department of Bioengineering Rice University Houston Texas 77005 USA

Two new compounds cadin-2-en-1β-ol-1β-D-glucuronopyranoside （1）, guaia-l,7-dien-3β,13-diol-13α-D- glucofuranoside （2） along with three known compounds have been isolated from the culture hairy roots of Catharanthus roseus. Their structures have been elucidated with the help of 500 MHz NMR using 1D and 2D spectral methods： viz： ^1H and ^13C NMR, ^1H-^1H COSY, ^1H-^13C HETCOR and DEPT aided by ELMS, FAB-MS, HR-FABMS and IR spectroscopy.

关键词： Catharanthus roseus Apocynaceae culture hairy root new constituent

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Abnormal Activity of Sympathetic Nervous System in Girls with Adolescent Idiopathic Scoliosis： A Cross-sectional Study

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Biomedical and Environmental Sciences 2018年第9期31卷 700-704页

作者： HU Zong Shan ZHAO Zhi Hui TSENG chang-chun LI Jie MAN Gene Chi-Wai LAM Tsz-Ping QIU Yong CHENG chun-yiu Jack ZHU Ze Zhang LIU Zhen Department of Orthopaedics and Traumatology Faculty of Medicine Prince of Wales Hospital The Chinese University of Hong Kong Shatin New Territories 999077 Hong Kong China The Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University Hong Kong 999077 China Department of Spine Surgery the Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008 Jiangsu China

The objective of this study was to characterize sympathetic nervous system （SNS） activity in girls with adolescent idiopathic scoliosis （AIS） and investigate the correlation of such activity with body weight and bone mass. Fifty-eight girls with AIS and 21 healthy controls were recruited. Abnormal growth pattern （lower weight, lower body mass index （BMI）, and longer arm span） and significantly increased adrenaline （AD） level, norepinephrine （NE） level, and low-frequency （LF） were found in girls with AIS. Circulating AD level, NE level, and LF power were negatively correlated with body weight and BMI but significantly correlated with bone quality.

关键词： AIS A Cross-sectional Study SNS BMD

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