Novel broad-spectrum antiviral compounds effective against Zika and SARS-CoV-2

Single-target drug and vaccine therapies are highly effective tools against novel and recurring viral strains circulating within human populations. These types of antiviral measures are often highly effective, with many of these types of drugs now being deployed to tackle long-standing human viruses, such as HIV and hepatitis.

Despite their usefulness and effectiveness, however, their specificity means these drugs can rarely be used against more than one pathogen, meaning that their applications tend to be limited. As such, developing broad-spectrum antiviral compounds is greatly important in tackling emerging viruses, especially now as the global coronavirus disease 2019 (COVID-19) pandemic continues, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

A research team at the University of Alberta, Canada, led by Dr. Daniel Limonta, has described two novel molecules with broad antiviral properties that are effective against a range of virus types, including SARS-CoV-2.

The research paper is available for early access reading on the American Society for Microbiology journal website.

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a protein receptor that recognizes the peptidoglycan muramyl dipeptide (MDP) found in certain bacteria and RNA viruses. In response to detecting MDP, NOD2 launches an immune response.

Expression of this immune response, referred to as the nodosome, however, was observed in previous work by Limonta and his team to actually promote replication of  Zika virus in human fetal brain cells. Zika virus belongs to the genus flavivirus, closely related to dengue fever, yellow fever, and other human pathogens. Developing an antiviral compound to suppress this response, therefore, may work to also slow or stop the replication of flaviviruses, and indeed other viruses of neighboring genera.

Limonta and colleagues used multiple human cell types and cell lines to identify two novel broad-spectrum antiviral NOD2 blocking drugs that inhibit the replication of a range of viruses: GSK717 and GSK583.

GSK717 inhibited replication of flaviviruses (the family that includes Zika and dengue), alphaviruses, enteroviruses, and SARS-CoV-2. GSK583 is a RIPK2 blocking agent (a critical mediator of NOD2 signaling) that potentially inhibits all these too, but was shown to be particularly effective against enteroviruses, the group that includes the common cold, polio, and hand-foot-and-mouth disease.

This type of broad-spectrum effectiveness is highly promising in the development of antiviral drug therapies, as these compounds may be used to prevent the replication of both recurring and emerging viruses.

During the initial outbreak of the SARS-CoV-2 pandemic, many patients relied on monoclonal antibodies sourced from recovered individuals, and only recently have specific vaccines been made widely available for the general public. Currently, only the antiviral drug remdesivir has shown promise as a broad-spectrum agent against SARS-CoV-2, so the development of more drugs with viral adaptability is key.

Research into antiviral drug therapies is especially relevant in terms of the current global context. Even before the COVID-19 pandemic, parts of the world have been subjected to local outbreaks of viruses such as yellow fever, HIV, and dengue. As SARS-CoV-2 currently sits at the forefront of the world’s medical research, producing compounds that successfully tackle this and other viral epidemics may end up producing large steps forward in the eradication of decades-long persisting viruses.

GSK717 and GSK583 are primarily anti-inflammatory drugs that additionally may benefit patients suffering from the inflammatory effects commonly associated with flavi-, alpha-, entero-, and coronaviruses.

The authors of the study, therefore, promote further research into the identification of broad-spectrum NOD2-suppressing antiviral compounds. Their study also highlights the potentially novel mechanism of NOD2 expression exploitation undertaken by novel viruses to evade immune responses.

Journal reference:
Michael Burgess

Written by

Michael Burgess

Michael graduated with a first-class degree in Zoology from the University of Hull, and later received a Masters degree in Palaeobiology from the University of Bristol.

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