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      Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

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          Abstract

          SARS-CoV-2 is the etiological agent responsible for the global COVID-19 outbreak. The main protease (M pro) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds ( 11a and 11b) targeting M pro. Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The X-ray crystal structures of SARS-CoV-2 M pro in complex with 11a or 11b, both determined at 1.5 Å resolution, showed that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of M pro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity, suggesting that these compounds are promising drug candidates.

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

              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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                Author and article information

                Journal
                Science
                Science
                SCIENCE
                Science (New York, N.y.)
                American Association for the Advancement of Science
                0036-8075
                1095-9203
                22 April 2020
                : eabb4489
                Affiliations
                [1 ]State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
                [2 ]School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
                [3 ]Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
                [4 ]State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
                [5 ]College of Pharmacy, Nanjing University of Chinese Medicine, Qixia District, Nanjing 210023, China.
                [6 ]National Chengdu Center for Safety Evaluation of Drugs, Westchina Hospital of Sichuan Unverisity, High-Tech Development Zone, Chengdu, Sichuan 610041, China.
                [7 ]State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300353, China.
                Author notes
                [*]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-8508-7130
                https://orcid.org/0000-0001-8556-8049
                https://orcid.org/0000-0002-7174-3851
                https://orcid.org/0000-0002-2932-2164
                https://orcid.org/0000-0001-6448-820X
                https://orcid.org/0000-0002-9400-308X
                https://orcid.org/0000-0003-1468-5568
                https://orcid.org/0000-0001-8175-5621
                https://orcid.org/0000-0003-3081-3750
                https://orcid.org/0000-0003-1705-4905
                https://orcid.org/0000-0001-5498-6942
                https://orcid.org/0000-0003-0656-6315
                https://orcid.org/0000-0001-9866-2384
                https://orcid.org/0000-0002-3120-3578
                https://orcid.org/0000-0002-1875-3268
                https://orcid.org/0000-0003-3685-6268
                Article
                abb4489
                10.1126/science.abb4489
                7179937
                32321856
                2fc2a9d0-95e1-408c-b88f-fee856dd63bc
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 18 March 2020
                : 20 April 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100014718, Innovative Research Group Project of the National Natural Science Foundation of China;
                Award ID: 21632008, 21672231, 21877118, 31970165, 81620108027
                Funded by: doi http://dx.doi.org/10.13039/501100003399, Science and Technology Commission of Shanghai Municipality;
                Award ID: 20431900100
                Funded by: doi http://dx.doi.org/10.13039/501100013290, National Key Research and Development Program of China Stem Cell and Translational Research;
                Award ID: 2017YFC0840300 and 2020YFA0707500
                Funded by: Chinese Academy of Engineering and Ma Yun Foundation;
                Funded by: Department of Science and Technology of Guangxi Zhuang Autonomous Region;
                Award ID: 2020AB40007
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                Biochem

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