Novel antiviral strategy for treatment of COVID-19

Date:
October 15, 2020
Source:
The University of Hong Kong
Summary:
Researchers have discovered a novel antiviral strategy for treatment
of COVID-19 using existing metallodrugs.



FULL STORY ==========================================================================
A research team led by Professor Hongzhe SUN, Norman & Cecilia Yip
Professor in Bioinorganic Chemistry, Department of Chemistry, Faculty of Science, and Professor Kwok Yung YUEN, Henry Fok Professor in Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine
of the University of Hong Kong (HKU), has discovered a novel antiviral
strategy for treatment of COVID-19.


==========================================================================
They discovered that a class of metallodrugs currently used in the
treatment of other infectious diseases is showing efficacy to potently
suppress SARS-CoV- 2 replication and relieve viral-associated symptoms
in an animal model.

The findings provide a new and readily available therapeutic option
with high clinical potential for infection with SARS-CoV-2. This ground-breaking work has been published online in a top-class scientific journal Nature Microbiology. A related patent has been filed in the US.

Background SARS-CoV-2 is an emerging coronavirus that has caused over
30 million laboratory-confirmed cases and more than 1 million deaths
globally of COVID-19 since December 2019. As the process of developing
an effective vaccine is still ongoing, another approach for prevention
and treatment of the disease is to identify anti-COVID-19 agents from
existing virus-specific antiviral drugs to repurpose their uses to
target the new virus. Remdesivir, a broad-spectrum antiviral drug,
has been reported to show efficacy towards SARS-CoV-2. However, global
shortage of the drug, its relatively high price and lack of significant clinical benefits in severe cases, are factors that have limited its wider applications. Clinical trials on a series of antiviral agents are still
ongoing which have yet to demonstrate therapeutic efficacies. Therefore, greater efforts are needed to extend the evaluation to cover a wider
spectrum of clinically approved drugs, which hopefully could open the
way to alternative treatment strategies against the disease through some readily available channels.

Study method and findings Generally, metal compounds are used as
anti-microbial agents; their antiviral activities have rarely been
explored. After screening a series of metallodrugs and related compounds,
the research team identified ranitidine bismuth citrate (RBC), a commonly
used anti-ulcer drug which contains the metal Bismuth for treatment of Helicobacter pylori-associated infection, as a potent anti-SARS- CoV-2
agent, both in vitro and in vivo.

RBC targets the vital non-structural protein 13 (Nsp13), a viral helicase essential for SARS-CoV-2 to replicate, by displacing the crucial zinc(II)
ions in the zinc-binding with Bismuth-ions, to potently suppress the
activity of the helicase.

RBC has been demonstrated to greatly reduce viral loads by over
1,000-folds in SARS-CoV-2-infected cells. In particular, in a golden
Syrian hamster model, RBC suppresses SARS-CoV-2 replications to reduce
viral loads by ~100 folds in both the upper and lower respiratory tracts,
and mitigates virus-associated pneumonia. RBC remarkably diminishes the
level of prognostic markers and other major pro-inflammatory cytokines
and chemokines in severe COVID-19 cases of infected hamsters, compared
to the Remdesivir-treated group and control group.

RBC exhibits a low cytotoxicity with a high selectivity index at 975
(the larger the number the safer the drug), as compared to Remdesivir
which has a low selectivity index at 129. The finding indicates a wide
window between the drug's cytotoxicity and antiviral activity, which
allows a great flexibility in adjusting its dosages for treatment.

The team investigated the mechanisms of RBC on SARS-CoV-2 and revealed for
the first time the vital Nsp13 helicase as a druggable target by RBC. It irreversibly kicks out the crucial zinc(II) ions in the zinc-binding
domain to change it to bismuth-bound via a distinct metal displacement
route. RBC and its Bi(III) compounds dysfuntionalised the Nsp13 helicase
and potently inhibited both the ATPase (IC50=0.69 myM) and DNA-unwinding (IC50=0.70 myM) activities of this enzyme.

The research findings highlight viral helicases as a druggable target, and
the high clinical potential of bismuth(III) drugs and other metallodrugs
for treatment of SARS-CoV-2 infections. Hopefully, following this
important breakthrough, more antiviral agents from readily available
clinically approved drugs could be identified for potential treatment
of COVID-19 infections. They can be in the form of combination regimens (cocktails) with drugs that exhibit anti-SARS-CoV-2 activities including
RBC, dexamethasone and interferon-b1b.


========================================================================== Story Source: Materials provided by The_University_of_Hong_Kong. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Shuofeng Yuan, Runming Wang, Jasper Fuk-Woo Chan, Anna Jinxia Zhang,
Tianfan Cheng, Kenn Ka-Heng Chik, Zi-Wei Ye, Suyu Wang, Andrew
Chak-Yiu Lee, Lijian Jin, Hongyan Li, Dong-Yan Jin, Kwok-Yung Yuen,
Hongzhe Sun.

Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2
replication and relieves virus-associated pneumonia in Syrian
hamsters. Nature Microbiology, 2020; DOI: 10.1038/s41564-020-00802-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201015101807.htm

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