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      In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

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          Abstract

          A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming stages of drug development. In this study, we screened the PRESTWICK CHEMICAL LIBRARY composed of 1,520 approved drugs in an infected cell-based assay. The robustness of the screen was assessed by the identification of drugs that already demonstrated in vitro antiviral effect against SARS-CoV-2. Thereby, 90 compounds were identified as positive hits from the screen and were grouped according to their chemical composition and their known therapeutic effect. Then EC50 and CC50 were determined for a subset of 15 compounds from a panel of 23 selected drugs covering the different groups. Eleven compounds such as macrolides antibiotics, proton pump inhibitors, antiarrhythmic agents or CNS drugs emerged showing antiviral potency with 2 < EC50 ≤ 20 µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study provides information for the selection of drugs to be further validated in vivo. Disclaimer: This study corresponds to the early stages of antiviral development and the results do not support by themselves the use of the selected drugs to treat SARS-CoV-2 infection.

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)
          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

            Qun Li, Xuhua Guan, Peng Wu … (2020)
            Abstract Background The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. Methods We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. Results Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). Conclusions On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.)
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              SARS and MERS: recent insights into emerging coronaviruses

              Emmie de Wit, Neeltje van Doremalen, Darryl Falzarano … (2016)
              Key Points Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic pathogens that can cause severe respiratory disease in humans. Although disease progression is fairly similar for SARS and MERS, the case fatality rate of MERS is much higher than that of SARS. Comorbidities have an important role in SARS and MERS. Several risk factors are associated with progression to acute respiratory distress syndrome (ARDS) in SARS and MERS cases, especially advanced age and male sex. For MERS, additional risk factors that are associated with severe disease include chronic conditions such as diabetes mellitus, hypertension, cancer, renal and lung disease, and co-infections. Although the ancestors of SARS-CoV and MERS-CoV probably circulate in bats, zoonotic transmission of SARS-CoV required an incidental amplifying host. Dromedary camels are the MERS-CoV reservoir from which zoonotic transmission occurs; serological evidence indicates that MERS-CoV-like viruses have been circulating in dromedary camels for at least three decades. Human-to-human transmission of SARS-CoV and MERS-CoV occurs mainly in health care settings. Patients do not shed large amounts of virus until well after the onset of symptoms, when patients are most probably already seeking medical care. Analysis of hospital surfaces after the treatment of patients with MERS showed the ubiquitous presence of infectious virus. Our understanding of the pathogenesis of SARS-CoV and MERS-CoV is still incomplete, but the combination of viral replication in the lower respiratory tract and an aberrant immune response is thought to have a crucial role in the severity of both syndromes. The severity of the diseases that are caused by emerging coronaviruses highlights the need to develop effective therapeutic measures against these viruses. Although several treatments for SARS and MERS (based on inhibition of viral replication with drugs or neutralizing antibodies, or on dampening the host response) have been identified in animal models and in vitro studies, efficacy data from human clinical trials are urgently required. Supplementary information The online version of this article (doi:10.1038/nrmicro.2016.81) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Franck Touret: franck.touret@univ-amu.fr
                Bruno Coutard: bruno.coutard@univ-amu.fr
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 4 August 2020
                Publication date PMC-release: 4 August 2020
                Publication date Collection: 2020
                Volume: 10
                Electronic Location Identifier: 13093
                Affiliations
                [1 ]ISNI 0000 0004 0519 5986, GRID grid.483853.1, Unité Des Virus Emergents (UVE: Aix Marseille Univ, IRD 190, INSERM 1207, IHU Méditerranée Infection), ; 13005 Marseille, France
                [2 ]ISNI 0000 0004 0572 0656, GRID grid.463833.9, Aix-Marseille Univ, INSERM U1068, CNRS UMR7258, Institut Paoli-Calmettes, CRCM, ; Marseille, France
                [3 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, Institut Français de Bioinformatique (IFB), UMS 3601-CNRS, , Université Paris-Saclay, ; Orsay, France
                [4 ]ISNI 0000 0001 2176 4817, GRID grid.5399.6, Aix-Marseille Univ, INSERM, Lab. Theory and Approaches of Genome Complexity (TAGC), ; Marseille, France
                [5 ]ISNI 0000 0001 2176 4817, GRID grid.5399.6, AFMB UMR 7257, , Aix-Marseille Université, CNRS, ; Marseille, France
                Article
                Publisher ID: 70143
                DOI: 10.1038/s41598-020-70143-6
                PMC ID: 7403393
                PubMed ID: 32753646
                SO-VID: fc0c9b65-2a51-4ecf-8c47-9b2049c1322f
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 12 May 2020
                Date accepted : 24 July 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/100010666, H2020 Research Infrastructures;
                Award ID: 871029
                Funded by: FundRef https://doi.org/10.13039/501100001677, Institut National de la Santé et de la Recherche Médicale;
                Award ID: REACTing
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Uncategorized
                Keywords: drug discovery,sars-cov-2
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: drug discovery, sars-cov-2

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