Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus.

doi:10.1016/J.JINF.2013.09.029

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Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus.

Journal Article•DOI•

Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus.

Jasper Fuk-Woo Chan¹, Kwok-Hung Chan¹, Richard Y.T. Kao¹, Kelvin K. W. To¹, Bo-Jian Zheng¹, Clara P. Y. Li¹, Patrick T.W. Li¹, Jun Dai¹, Florence K.Y. Mok¹, Honglin Chen¹, Frederick G. Hayden², Kwok-Yung Yuen¹ - Show less +8 more•Institutions (2)

University of Hong Kong¹, University of Virginia²

01 Dec 2013-Journal of Infection (J Infect)-Vol. 67, Iss: 6, pp 606-616

TL;DR: Assessment of the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays suggests Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.

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About: This article is published in Journal of Infection.The article was published on 2013-12-01 and is currently open access. It has received 316 citations till now. The article focuses on the topics: Coronavirus & Middle East respiratory syndrome coronavirus.

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Journal Article•DOI•

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

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Bin Cao¹, Yeming Wang¹, Danning Wen², Wen Liu², Jingli Wang², Guohui Fan¹, Lianguo Ruan², Bin Song², Yanping Cai², Ming Wei², Xingwang Li³, Jia'an Xia², Nanshan Chen², Jie Xiang¹, Ting Yu², Tao Bai², Xuelei Xie², Li Zhang¹, Caihong Li², Ye Yuan², Hua Chen², Huadong Li², Hanping Huang², Shengjing Tu², Fengyun Gong², Ying Liu², Yuan Wei², Chongya Dong⁴, Fei Zhou¹, Xiaoying Gu¹, Jiuyang Xu⁵, Zhibo Liu¹, Yi Zhang¹, Li Hui¹, Lianhan Shang¹, Ke Wang², Kunxia Li², Xia Zhou², Xuan Dong², Zhaohui Qu¹, Sixia Lu², Xujuan Hu², Shunan Ruan², Shanshan Luo, Jing Wu², Lu Peng², Fang Cheng², Lihong Pan², Jun Zou², Chunmin Jia², Juan Wang², Xia Liu², Shuzhen Wang², Xudong Wu², Qin Ge², Jing He², Haiyan Zhan², Fang Qiu², Li Guo⁶, Chaolin Huang¹, Thomas Jaki¹, Frederick G. Hayden¹, Peter Horby⁷, Dingyu Zhang¹, Chen Wang¹ - Show less +61 more•Institutions (7)

China-Japan Friendship Hospital¹, Wuhan Jinyintan Hospital², Capital Medical University³, Peking University⁴, Tsinghua University⁵, Peking Union Medical College⁶, University of Oxford⁷

18 Mar 2020-The New England Journal of Medicine

TL;DR: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care, and future trials in patients withsevere illness may help to confirm or exclude the possibility of a treatment benefit.

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Abstract: Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involvin...

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4,293 citations

Journal Article•DOI•

SARS and MERS: recent insights into emerging coronaviruses

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Emmie de Wit¹, Neeltje van Doremalen¹, Darryl Falzarano², Vincent J. Munster¹•Institutions (2)

National Institutes of Health¹, Vaccine and Infectious Disease Organization²

27 Jun 2016-Nature Reviews Microbiology

TL;DR: The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronav virus into the human population in the twenty-first century, and the current state of development of measures to combat emerging coronaviruses is discussed.

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Abstract: The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiology and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses.

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2,794 citations

Journal Article•DOI•

Emerging coronaviruses: Genome structure, replication, and pathogenesis.

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Yu Chen¹, Qianyun Liu¹, Deyin Guo²•Institutions (2)

Wuhan University¹, Sun Yat-sen University²

01 Apr 2020-Journal of Medical Virology

TL;DR: This review will help understand the biology and potential risk of CoVs that exist in richness in wildlife such as bats and describe diseases caused by different CoVs in humans and animals.

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Abstract: The recent emergence of a novel coronavirus (2019-nCoV), which is causing an outbreak of unusual viral pneumonia in patients in Wuhan, a central city in China, is another warning of the risk of CoVs posed to public health. In this minireview, we provide a brief introduction of the general features of CoVs and describe diseases caused by different CoVs in humans and animals. This review will help understand the biology and potential risk of CoVs that exist in richness in wildlife such as bats.

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2,480 citations

Journal Article•DOI•

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

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Waleed Alhazzani¹, Morten Hylander Møller², Yaseen M. Arabi³, Mark Loeb¹, Michelle Ng Gong⁴, Eddy Fan⁵, Simon Oczkowski¹, Mitchell M. Levy⁶, Mitchell M. Levy⁷, Lennie P. G. Derde⁸, Lennie P. G. Derde⁹, Amy L. Dzierba¹⁰, Bin Du¹¹, Michael S. Aboodi⁴, Hannah Wunsch¹², Hannah Wunsch⁵, Maurizio Cecconi¹³, Younsuck Koh¹⁴, Daniel S. Chertow¹⁵, Kathryn Maitland¹⁶, Fayez Alshamsi¹⁷, Emilie P. Belley-Côté¹⁸, Emilie P. Belley-Côté¹, Massimiliano Greco¹³, Matthew Laundy¹⁹, Jill S. Morgan²⁰, Jozef Kesecioglu⁹, Allison McGeer⁵, Leonard A. Mermel⁷, Manoj J. Mammen²¹, Paul E. Alexander¹, Amy S. Arrington²², John Centofanti¹, Giuseppe Citerio²³, Bandar Baw²⁴, Bandar Baw¹, Ziad A. Memish²⁵, Naomi E Hammond²⁶, Naomi E Hammond²⁷, Frederick G Hayden²⁸, Laura Evans²⁹, Andrew Rhodes¹⁹ - Show less +38 more•Institutions (29)

McMaster University¹, Copenhagen University Hospital², King Saud bin Abdulaziz University for Health Sciences³, Albert Einstein College of Medicine⁴, University of Toronto⁵, Rhode Island Hospital⁶, Brown University⁷, Oklahoma State University Center for Health Sciences⁸, Utrecht University⁹, NewYork–Presbyterian Hospital¹⁰, Peking Union Medical College Hospital¹¹, Sunnybrook Health Sciences Centre¹², Humanitas University¹³, University of Ulsan¹⁴, National Institutes of Health¹⁵, Imperial College London¹⁶, United Arab Emirates University¹⁷, Population Health Research Institute¹⁸, St George’s University Hospitals NHS Foundation Trust¹⁹, Emory University Hospital²⁰, University at Buffalo²¹, Baylor College of Medicine²², University of Milano-Bicocca²³, King Abdulaziz Medical City²⁴, King Saud Medical City²⁵, The George Institute for Global Health²⁶, Royal North Shore Hospital²⁷, University of Virginia²⁸, University of Washington²⁹

28 Mar 2020-Intensive Care Medicine

TL;DR: The Surviving Sepsis Campaign CO VID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19, and will provide new recommendations in further releases of these guidelines.

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Abstract: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy. The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines.

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1,762 citations

Cites result from "Broad-spectrum antivirals for the e..."

...In vitro data showed that rIFN-β displayed the strongest MERS-CoV inhibition among different rIFN preparations (rIFN-α2b, rIFN-γ, rIFN-universal, and rIFN-α2a , rIFN-β), at 41 times lower than the previously reported 50% inhibitory concentration (IC50) of rIFN-α2b [203, 205] ....
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Journal Article•DOI•

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.

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Canrong Wu¹, Yang Liu², Yueying Yang², Peng Zhang², Wu Zhong, Yali Wang², Qiqi Wang², Yang Xu², Mingxue Li², Xing-Zhou Li, Mengzhu Zheng¹, Lixia Chen², Hua Li¹, Hua Li² - Show less +10 more•Institutions (2)

Huazhong University of Science and Technology¹, Shenyang Pharmaceutical University²

27 Feb 2020-Acta Pharmaceutica Sinica B

TL;DR: This study systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling and constructed a database of 78 commonly used anti-viral drugs.

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1,680 citations

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Journal Article•DOI•

Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia

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Ali Moh Zaki, Sander van Boheemen¹, Theo M. Bestebroer¹, Albert D. M. E. Osterhaus, Ron A. M. Fouchier - Show less +1 more•Institutions (1)

Erasmus University Rotterdam¹

07 Nov 2012-The New England Journal of Medicine

TL;DR: The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.

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Abstract: A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.

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4,809 citations

"Broad-spectrum antivirals for the e..." refers methods in this paper

...Zaki, and colleagues.(3) The isolate was amplified by one additional passage in Vero cells to make working stocks of the virus (4 10(5) TCID50/ml)....
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Journal Article•DOI•

Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

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V. Stalin Raj¹, Huihui Mou², Saskia L. Smits¹, Dick H. W. Dekkers¹, Marcel A. Müller³, Ronald Dijkman⁴, Doreen Muth³, Jeroen Demmers¹, Ali Moh Zaki, Ron A. M. Fouchier¹, Volker Thiel⁴, Volker Thiel⁵, Christian Drosten³, Peter J. M. Rottier², Albert D. M. E. Osterhaus¹, Berend Jan Bosch², Bart L. Haagmans¹ - Show less +13 more•Institutions (5)

Erasmus University Rotterdam¹, Utrecht University², University of Bonn³, University of St. Gallen⁴, University of Zurich⁵

14 Mar 2013-Nature

TL;DR: Dipeptidyl peptidase 4 (DPP4; also known as CD26) is identified as a functional receptor for hCoV-EMC and will contribute critically to the understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.

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Abstract: Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals. However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection. Viral genome analysis revealed close relatedness to coronaviruses found in bats. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.

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1,743 citations

"Broad-spectrum antivirals for the e..." refers background in this paper

...Other agents with in vitro anti-SARS-CoV activities such as glycyrrhizin, baicalin, reserpine, aescin, valinomycin, niclosamide, aurintricarboxylic acid, mizoribine, indomethacin, chloroquine, and experimental agents like small interfering RNA (siRNA) and inhibitors targeting the binding interface between the S1 domian and receptor in vivo, should also be evaluated.(34,35,71) We did not test these agents in this study because most of them have the problems of either not being commercially available or having therapeutic levels that are not easily achievable clinically....
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Journal Article•DOI•

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.

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Chung-Ming Chu¹, V C C Cheng², Ivan Hung², M M L Wong³, K H Chan², K S Chan¹, Richard Y.T. Kao², Leo L.M. Poon², C L P Wong², Yi Guan², Joseph S. M. Peiris², Kwok-Yung Yuen² - Show less +8 more•Institutions (3)

United Christian Hospital¹, University of Hong Kong², Caritas Medical Centre³

01 Mar 2004-Thorax

TL;DR: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS and shows that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome.

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Abstract: Background: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. Methods: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. Results: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 µg/ml and 50 µg/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p Conclusions: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.

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1,435 citations

"Broad-spectrum antivirals for the e..." refers methods in this paper

...Additionally, we tested other agents reported to have in vitro activities against SARS-CoV and/or MERSCoV.32,34,40 Imukin (interferon-g1b) and the HIV protease inhibitors, nelfinavir mesylate hydrate and lopinavir, showed suboptimal EC50 in the initial CPE inhibition assay and were therefore not further evaluated....
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...PRA was performed as we previously described with modifications.(32) Briefly, it was performed in duplicate in 24well tissue culture plates (TPP)....
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...Additionally, we tested other agents reported to have in vitro activities against SARS-CoV and/or MERSCoV.(32,34,40) Imukin (interferon-g1b) and the HIV protease inhibitors, nelfinavir mesylate hydrate and lopinavir, showed suboptimal EC50 in the initial CPE inhibition assay and were therefore not further evaluated....
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Journal Article•DOI•

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

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Abdullah M. Assiri, Jaffar A. Al-Tawfiq¹, Abdullah A Al-Rabeeah, Fahad Alrabiah, Sami Al-Hajjar, Ali Albarrak², Hesham Flemban, Wafa N. Al-Nassir³, Hanan H. Balkhy⁴, Rafat F. Alhakeem, Hatem Q. Makhdoom, Alimuddin Zumla⁵, Alimuddin Zumla⁶, Ziad A. Memish⁷ - Show less +10 more•Institutions (7)

Saudi Aramco¹, King Saud Medical City², National Guard Health Affairs³, King Abdulaziz Medical City⁴, University College London Hospitals NHS Foundation Trust⁵, University College London⁶, Alfaisal University⁷

01 Sep 2013-Lancet Infectious Diseases

TL;DR: Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities, and major gaps in knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition.

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Abstract: Summary Background Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). Clinical data on MERS-CoV infections are scarce. We report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of MERS-CoV infections, identify knowledge gaps, and define research priorities. Methods We abstracted and analysed epidemiological, demographic, clinical, and laboratory data from confirmed cases of sporadic, household, community, and health-care-associated MERS-CoV infections reported from Saudi Arabia between Sept 1, 2012, and June 15, 2013. Cases were confirmed as having MERS-CoV by real-time RT-PCR. Findings 47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age. Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]). All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]). Interpretation Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition. Funding None.

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1,275 citations

"Broad-spectrum antivirals for the e..." refers background in this paper

...Unlike most other human coronavirus infections which are generally mild, most patients with MERS have suffered from rapidly progressive pneumonia with some also developing acute renal failure, hepatic dysfunction, gastrointestinal upset, pericarditis, disseminated intravascular coagulation, and/or cytopenias.(2,24) The resulting crude mortality rate of nearly 50% in documented cases far exceeded those seen in all other human coronavirus infections including SARS despite aggressive supportive treatment including extracorporeal membrane oxygenation in some of the MERS cases....
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...Furthermore, the use of ribavirin, and hence also its combination with interferon-a2b, may be limited in the clinical setting, because a significant proportion of patients with MERS-CoV infection have developed acute renal failure often requiring renal replacement therapy.(2,24) It has been suggested that systemic ribavirin should best be avoided in patients with a creatinine clearance of <50 ml/min because of the increased risk of haemolytic anaemia....
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Journal Article•DOI•

Mycophenolate mofetil and its mechanisms of action.

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Anthony C. Allison, Elsie M. Eugui¹•Institutions (1)

Hoffmann-La Roche¹

01 May 2000-Immunopharmacology

TL;DR: The efficacy of regimes including CellCept(R) in preventing allograft rejection, and in the treatment of rejection, is now firmly established and it is hoped that the drug will have the same effect in humans.

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1,238 citations

"Broad-spectrum antivirals for the e..." refers background in this paper

...However, the risk of immunosuppression at the onset of adaptive immune responses or polarization towards a deleterious Th1 response by mycophenolic acid needs to be considered.(60) One possible approach is a short course of mycophenolate mofetil combined with an interferon, particularly interferon-b1b, to provide synergistic antiviral and immune-enhancing effects against MERS-CoV....
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