Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus infecting humans and livestock worldwide. Not all coronavirus infections cause major symptoms but some like SARS-CoV-2, SARS-CoV, and MERS-CoV can cause serious disease. To date, the SARS-CoV-2 pandemic has caused more than 250 million infections and five million deaths worldwide. Coronavirus infections in livestock are zoonotic in origin and could lead to more outbreaks in the future. Therefore, it became necessary to screen for effective pan-inhibitors for emerging coronaviruses like SARS-CoV-2.
Study: Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease. Image Credit: Lightspring/ Shutterstock
Earlier it was believed that the RNA-dependent RNA polymerase inhibitor, Remdesivir may be an effective treatment option for patients infected with SARS-CoV-2. However, clinical trials of Remdesivir were not very successful and prompted more screening for ideal antiviral agents, specifically pan-inhibitors of coronaviruses.
SARS-CoV-2 belongs to the Coronaviridae family with a unique life cycle and is a positive RNA virus. Immediately after entry into host cells, coronaviruses translate two polyproteins into nonstructural proteins with the help of protease (Mpro or 3CLpro) and papain-like protease (PLpro). Given the crucial role of the main protease (Mpro) in the replication and transcription of the virus, targeting Mpro chemically may help in inhibiting multiple coronaviruses.
In a paper published in the International Journal of Molecular Sciences, researchers from China reported the results of their study aimed at finding an effective Mpro inhibitor since Mpro is the best drug target to fight SARS-CoV-2 infection.
The study
Many natural products obtained from plants and animals have antiviral and antioxidant properties. The researchers screened natural products for Mpro inhibitors. They found that Xanthohumol, a compound extracted from hops plant (Humulus lupulus) that contributes to bitterness in beer, is a potent inhibitor of Mpro. Previous studies have reported the antiviral, antioxidant, and anti-cancer properties of Xanthohumol. In-vitro study of Xanthohumol demonstrated that it could suppress Mpro hydrolase activity at low concentrations.
Cell-based assays showed that while Xanthohumol can decrease cell viability at high concentrations, it could not reduce cell growth. Plague assays revealed that Mpro plays an important role in viral RNA replication as it cleaves the viral polyproteins for assembly of the replication machinery. This encouraged the researchers to use Xanthohumol as a Mpro inhibitor of SARS-CoV-2 and evaluate its efficacy. The results showed that Xanthohumol is a potent Mpro inhibitor for SARS-CoV-2 and can eliminate the viral genome. These findings were consistent with and supported the results of the plague assay. Overall, Xanthohumol was found to be effective against SARS-CoV-2.
A similar study was conducted to evaluate the efficiency of Xanthohumol against the porcine epidemic diarrhea virus (PEDV) by using PEDV Mpro in place of SARS-CoV-2 Mpro. Similar results were obtained for PEDV as well. From the results of the cell-based assay, the researchers concluded that Xanthohumol is a potent inhibitor of coronavirus and PEDV Mpro. According to the authors, Xanthohumol should be further developed to effectively treat patients infected by alpha and beta mutants of SARS-CoV-2.
Limitations and future scope
Although the findings show that Xanthohumol is effective against coronaviruses at lower concentrations, more detailed systematic studies on the use of Xanthohumol are necessary before it can be used for medicinal purposes.
Researchers are still trying to understand the underlying mechanism of viral inhibition by Xanthohumol or its role in coronavirus disease 2019 (COVID-19) treatment. They suggest that the protease inhibiting property of Xanthohumol can also be used in treating other diseases like HIV, HCV, and porcine reproductive and respiratory syndrome virus (PRRSV) through a similar inhibitor mechanism. Increasing numbers of SARS-CoV-2 infections worldwide have facilitated mutation of SARS-CoV-2 and the emergence of many viral variants.
Due to their zoonotic origin, coronaviruses may cause more outbreaks in the future, and thus it is necessary to keep screening for potent inhibitors of these viruses. Future trials focusing on coronavirus infections could provide more information on whether the findings of this study are useful for the development of pan-inhibitors against different coronaviruses. To conclude, the researchers believe that Xanthohumol is a potent inhibitor of Mpro SARS-CoV-2 as shown in their in vitro and cell-based assays and suggest that it should be further developed clinically.
Global study reveals mismatch in COVID-19 treatment guidelines with WHO standards