A research team led by Professor Hongzhe SUN, Norman & Cecilia Yip, Professor of Bioinorganic Chemistry, Department of Chemistry, Faculty of Science, and Professor Kwok Yung YUEN, Henry Fok, Professor of Infectious Diseases, Department of Microbiology, Li Ka Shing, Faculty for Medicine The University of Hong Kong (HKU) has discovered a novel antiviral strategy to treat COVID-19.
The results offer a new and readily available treatment option with high clinical potential for SARS-CoV-2 infection. This groundbreaking work was published online in a high profile scientific journal Natural microbiology. A corresponding patent has been applied for in the USA.
background
SARS-CoV-2 is a emerging coronavirus that has caused over 30 million laboratory-confirmed cases and more than 1 million deaths from COVID-19 worldwide since December 2019. With the development of an effective vaccine ongoing, there is yet another approach to prevention and treatment for the disease is to identify anti-COVID-19 agents from existing virus-specific antiviral drugs in order to use them to fight the new virus reuse. Remdesivir, a broad spectrum antiviral drug, has been reported to be effective against SARS-CoV-2. However, the global shortage of the drug, its relatively high price, and the lack of significant clinical benefits in severe cases are factors that have limited its wider uses. Clinical studies are still ongoing with a number of antiviral agents that are not yet therapeutically effective. Therefore, greater efforts are required to extend the evaluation to a wider range of clinically approved drugs, which hopefully could pave the way for alternative treatment strategies for the disease through some readily available channels.
Investigation method and results
In general, metal compounds are used as antimicrobial agents; Their antiviral activities have rarely been studied. After screening a number of metallodrugs and related compounds, the research team identified ranitidine bismuth citrate (RBC), a commonly used anti-ulcer drug that contains the metal bismuth used to treat Helicobacter pylori-associated infections, as an effective anti-SARS-CoV-2 Means, both in vitro and in vivo.
RBC targets the vital non-structural protein 13 (Nsp13), a viral helicase essential for SARS-CoV-2 replication by displacing the critical zinc (II) ions in the zinc bond with bismuth for activity effective to suppress the helicase.
RBC has been shown to greatly reduce viral load in SARS-CoV-2 infected cells by 1000-fold. In a Syrian golden hamster model in particular, RBC suppresses SARS-CoV-2 replications to reduce viral loads in both the upper and lower airways by ~ 100-fold and to alleviate virus-associated pneumonia. RBC significantly reduces the level of prognostic markers and other important pro-inflammatory cytokines and chemokines in severe COVID-19 cases of infected hamsters compared to the remdesivir-treated group and control group.
RBC shows low cytotoxicity with a high selectivity index at 975 (the larger the number, the safer the drug) compared to remdesivir which has a low selectivity index at 129. The finding shows a wide window between the drug’s cytotoxicity and its antiviral activity. This allows great flexibility in adjusting the dosages for the treatment.
The team examined the mechanisms of RBC on SARS-CoV-2, and for the first time revealed the vital Nsp13 helicase as a drugable target of RBC. It irreversibly ejects the crucial zinc (II) ions in the zinc binding domain in order to convert them into bismuth-bound ones via a certain metal displacement path. RBC and its Bi (III) compounds have dysfunctionalized the Nsp13 helicase and effectively inhibited both the ATPase (IC50 = 0.69 µM) and DNA processing activities (IC50 = 0.70 µM) of this enzyme.
Research highlights viral helicases as a drug target and the high clinical potential of bismuth (III) drugs and other metal drugs for the treatment of SARS-CoV-2 infections. After this important breakthrough, hopefully more antivirals could be identified from readily available clinically approved drugs for potential treatment of COVID-19 infections. They can be in the form of combination schemes (cocktails) with drugs that have anti-SARS-CoV-2 activities, including RBC, dexamethasone, and interferon-β1b.
Materials provided by The University of Hong Kong. Note: The content can be edited by style and length.
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