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

Na Zhu, Dingyu Zhang, Wenling Wang … (2020)

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

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

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

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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Journal

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Journal ID (publisher-id): SCIENCE

Title: Science (New York, N.y.)

Publisher: American Association for the Advancement of Science

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date (Electronic): 22 April 2020

Electronic Location Identifier: 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.

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[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: hliu@ 123456simm.ac.cn (H.L.); yanght@ 123456shanghaitech.edu.cn (H.Y.); zhangleike@ 123456wh.iov.cn (L.-K.Z.); ycxu@ 123456simm.ac.cn (Y.X.)

Author information

Wenhao Dai https://orcid.org/0000-0001-8508-7130

Bing Zhang https://orcid.org/0000-0001-8556-8049

Haixia Su https://orcid.org/0000-0002-7174-3851

Yao Zhao https://orcid.org/0000-0002-2932-2164

Zhenming Jin https://orcid.org/0000-0001-6448-820X

Fengjiang Liu https://orcid.org/0000-0002-9400-308X

Fang Bai https://orcid.org/0000-0003-1468-5568

Haofeng Wang https://orcid.org/0000-0001-8175-5621

Xi Cheng https://orcid.org/0000-0003-3081-3750

Jiang Wang https://orcid.org/0000-0003-1705-4905

Xiang Liu https://orcid.org/0000-0001-5498-6942

Hualiang Jiang https://orcid.org/0000-0003-0656-6315

Zihe Rao https://orcid.org/0000-0001-9866-2384

Yechun Xu https://orcid.org/0000-0002-3120-3578

Haitao Yang https://orcid.org/0000-0002-1875-3268

Hong Liu https://orcid.org/0000-0003-3685-6268

Article

Publisher ID: abb4489

DOI: 10.1126/science.abb4489

PMC ID: 7179937

PubMed ID: 32321856

SO-VID: 2fc2a9d0-95e1-408c-b88f-fee856dd63bc

Copyright © 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).

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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

Date received : 18 March 2020

Date accepted : 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;

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

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Novel Coronavirus Disease COVID-19

Most cited references 16

A Novel Coronavirus from Patients with Pneumonia in China, 2019

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

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