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Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

View ORCID ProfileGuanguan Li, Jing Sun, Yingjun Li, Yongjie Shi, Jincun Zhao, Tony Y. Zhang, Xumu Zhang
doi: https://doi.org/10.1101/2020.05.26.114033
Guanguan Li
1Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, Guangzhou 518055, China
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  • ORCID record for Guanguan Li
Jing Sun
3State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, China
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Yingjun Li
1Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, Guangzhou 518055, China
2Medi-X and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangzhou 518055, China
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Yongjie Shi
1Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, Guangzhou 518055, China
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Jincun Zhao
3State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, China
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Tony Y. Zhang
4Tyligand Bioscience (Shanghai) Limited, Shanghai, China
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  • For correspondence: tony@tyligand.com zhangxm@sustech.edu.cn
Xumu Zhang
1Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, Guangzhou 518055, China
2Medi-X and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangzhou 518055, China
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  • For correspondence: tony@tyligand.com zhangxm@sustech.edu.cn
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ABSTRACT

In all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S- enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) were found to be 27% and 60% more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. With these data and previous work on stereoselective metabolism of CQ and HCQ, we recommend that future clinical studies should employ S-HCQ as a potentially superior drug substance for the treatment of COVID-19 for improved therapeutic index.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 27, 2020.
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Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19
Guanguan Li, Jing Sun, Yingjun Li, Yongjie Shi, Jincun Zhao, Tony Y. Zhang, Xumu Zhang
bioRxiv 2020.05.26.114033; doi: https://doi.org/10.1101/2020.05.26.114033
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Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19
Guanguan Li, Jing Sun, Yingjun Li, Yongjie Shi, Jincun Zhao, Tony Y. Zhang, Xumu Zhang
bioRxiv 2020.05.26.114033; doi: https://doi.org/10.1101/2020.05.26.114033

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