Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2
Ou et al.
, Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2
, PLOS Pathogens, doi:10.1371/journal.ppat.1009212 (date from earlier preprint) (In Vitro)
analysis showing that HCQ efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of HCQ and a TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone.14 In Vitro studies
support the efficacy of HCQ [Andreani, Clementi, Dang, Delandre, Faísca, Hoffmann, Liu, Ou, Purwati, Sheaff, Wang, Wang (B), Yao, Yuan]
Ou et al., 22 Jul 2020, peer-reviewed, 6 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: PLOS PATHOGENS
Hydroxychloroquine-mediated inhibition of
SARS-CoV-2 entry is attenuated by TMPRSS2
Tianling Ou*, Huihui Mou, Lizhou Zhang, Amrita Ojha, Hyeryun Choe, Michael Farzan ID*
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, United States
* firstname.lastname@example.org (TO); email@example.com (MF)
Citation: Ou T, Mou H, Zhang L, Ojha A, Choe H,
Farzan M (2021) Hydroxychloroquine-mediated
inhibition of SARS-CoV-2 entry is attenuated by
TMPRSS2. PLoS Pathog 17(1): e1009212. https://
Editor: Benhur Lee, Icahn School of Medicine at
Mount Sinai, UNITED STATES
Received: July 19, 2020
Accepted: December 3, 2020
Published: January 19, 2021
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
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editorial history of this article is available here:
Copyright: © 2021 Ou et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in
any medium, provided the original author and
source are credited.
Data Availability Statement: All relevant data are
within the manuscript and the Supporting
Funding: This work is supported by an emergency
administrative supplement to NIH R01 AI129868.
Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness
as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins,
thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of
SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furincleavage site of the SARS-CoV-2 S protein is ablated or when it is introduced into the
SARS-CoV-1 S protein. We also show that hydroxychloroquine efficiently blocks viral entry
mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more
potently than either drug alone. These studies identify functional differences between
SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited
in vivo utility of hydroxychloroquine as a treatment for COVID-19.
The novel pathogenic coronavirus SARS-CoV-2 causes COVID-19 and remains a threat
to global public health. Chloroquine and hydroxychloroquine have been shown to prevent
viral infection in cell-culture systems, but human clinical trials did not observe a significant improvement in COVID-19 patients treated with these compounds. Here we show
that hydroxychloroquine interferes with only one of two..
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