Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication
Malla et al.,
Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication,
bioRxiv, doi:10.1101/2021.05.02.442358 (Preprint)
In Vitro study showing that vitamin C inhibits SARS-CoV-2 3CLpro. Authors note that the different clinical results may be explained in part by the widely varying dosages used, and they conclude that vitamin C and/or derivatives may become an important treatment for COVID-19 and other viral infections.
Malla et al., 3 May 2021, preprint, 9 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2021.05.02.442358; this version posted May 20, 2021. The copyright holder for this preprint (which
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
available under aCC-BY-NC-ND 4.0 International license.
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Vitamin C Binds to SARS Coronavirus-2 Main Protease Essential for Viral
Replication
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Tek Narsingh Malla1&, Suraj Pandey1&, Luis Aldama2, Dennisse Feliz2, 3, Moraima Noda2,
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Ishwor Poudyal1, George N. Phillips Jr.4, Emina A. Stojković2*, Marius Schmidt1*
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Department of Physics, University of Wisconsin Milwaukee, Milwaukee, WI 53211 USA
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Department of Biology, Northeastern Illinois University, Chicago, IL 60625 USA
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Department of Chemistry, Northeastern Illinois University, Chicago, IL 60625 USA
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Department of BioSciences, Rice University, Houston, TX 77005 USA
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&
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*corresponding authors
contributed equally
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Abstract
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There is an urgent need for anti-viral agents that treat and/or prevent Covid-19 caused by SARS-
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Coronavirus (CoV-2) infections. The replication of the SARS CoV-2 is dependent on the activity
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of two cysteine proteases, a papain-like protease, PL-pro, and the 3C-like protease known as
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main protease Mpro or 3CLpro. The shortest and the safest path to clinical use is the repurposing
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of drugs with binding affinity to PLpro or 3CLpro that have an established safety profile in
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humans. Several studies have reported crystal structures of SARS-CoV-2 main protease in
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complex with FDA approved drugs such as those used in treatment of hepatitis C. Here, we
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report the crystal structure of 3CLpro in complex Vitamin C (L-ascorbate) bound to the protein's
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active site at 2.5 Ångstrom resolution. The crystal structure of the Vitamin C 3CLpro complex
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may aid future studies on the effect of Vitamin C not only on the coronavirus main protease but
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on related proteases of other infectious viruses.
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bioRxiv preprint doi: https://doi.org/10.1101/2021.05.02.442358; this version posted May 20, 2021. The copyright holder for this preprint (which
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
available under aCC-BY-NC-ND 4.0 International license.
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a
ASC
FTE
His41
His163
Cys145
subunit A
subunit B
b
FTE
c
ASC
DTT
His41 Cys145
Cys145
His163
His41
His163
Figure 1. Vitamin C and DTT bound in the active site of SARS CoV-2 3CLpro. (a) The
3CLpro dimer in the asymmetric unit of the orthorhombic crystals soaked with L-ascorbate.
Polder difference electron density (Liebschner et al., 2017) in the active sites is shown in
green (contour: 2.5 sigma). (b) The L-ascorbate (ASC) in subunit B. The ASC interacts
with the catalytic Cys-145 and is stabilized by a hydrogen bond to His-163. A
trifluoroethanol (FTE) is located close to the ASC. (c) Dithiothreitol (DTT) is observed in
monoclinic (C2) crystal form. It does not bind to Cys-41. It rather binds to His-41 forming a
sulfenamide. Difference electron density maps shown in (a) - (c) are obtained after refining
the 3CLpro without the addition of ligand. The ascorbate and DTT explain the additional
electron density.
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The Covid-19 pandemic, caused by a novel severe acute respiratory syndrome (SARS)
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coronavirus 2, has paralyzed public life..
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