Probenecid has been shown to be effective against respiratory syncytial virus.

The respiratory syncytial virus (RSV) is one of the most frequent viruses that causes viral respiratory illness, with the largest burden of disease in newborns and young children.

Many researchers have attempted to alleviate the problem by developing RSV vaccinations and antivirals. The antiviral action of the licenced medicine probenecid against this virus has now been described in a recent research published online in the journal Viruses.

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Introduction

RSV is responsible for nearly 150,000 hospitalizations in children each year, costing the healthcare system hundreds of millions of dollars.

Only ribavirin and palivizumab have been shown to be effective against RSV so far, with variable results. Indeed, resistance mutations to the latter, which must be administered monthly by injection to high-risk newborns throughout the RSV season, would significantly lower its effectiveness from the present 50% reduction in RSV-related infant hospitalizations.

Repurposing is a common practise in which already-approved medications are effectively shown to be beneficial for a different application, reducing drug research costs and speeding up approval and marketing. One method is to look at the mechanisms through which viruses interact with their hosts in order to find druggable targets.

Finding a host cell protein essential for viral replication, for example, might lead to the development of a medication that targets that protein.

This might aid in the development of an antiviral that works against different viruses via a single mechanism. The researchers used high-throughput screening (HTS) and RNA interference (RNAi) to mute certain host genes and so determine which host genes and cellular pathways are essential as druggable antiviral targets in the present study.

The present research expands on previous work by the same group to identify genes that may be involved in the prevention of influenza A virus (IAV) replication. They discovered that the organic anion transporter-3 (OAT3) gene is required for this process, and that probenecid, an authorised uricosuric medication, inhibits the OAT3 or SLC22A8 gene.

Probenecid was able to significantly inhibit IAV replication in cell cultures and mice in this fashion. Humans and mice share the SLC gene family. IAV replication was inhibited when cells in culture were induced to produce siRNA that targeted the OAT3 gene. The failure of OAT1, OAT2, OAT4, and OAT7 inhibitors to obtain the same outcome demonstrated the specificity of this activity.

Probenecid is used to treat gout and is involved in both uric acid excretion in the urine and OAT3 inhibition. It is generally accepted and has minimal side effects, although its activity on other ion channels may have further effects on the inflammatory system. The fact that it does not target RNA-dependent RNA polymerase drew the present group of experts' attention.

Findings

RSV replication was significantly reduced when probenecid was used in three separate cell lines and animals, as predicted from previous research using influenza virus and the presently circulating severe acute respiratory syndrome coronavirus 2. (SARS-CoV-2). There was no evidence of toxicity.

The medication was effective against both RSV A and RSV B. RSV-infected mice showed similar outcomes, with a substantial decrease in viral burden. This was accomplished by lowering OAT3 expression. When cells were pretreated with probenecid, they were resistant to RSV replication, with half-maximal inhibitory concentrations (IC50) of 0.1 uM for RSV A2 and 0.85 uM for RSV B1.

To put it another way, this medicine inhibited RSV replication at nanomolar concentrations, which is a lot lower than the dose necessary to stop IAV replication. Both pre-treatment and post-exposure injection of probenecid reduced lung virus titers, indicating that this medicine has both preventive and therapeutic efficacy in RSV infection.

Implications

The researchers claim that

According to the findings, nanomolar dosages of all probenecid regimens limit RSV strain A and B replication in vitro and RSV strain A replication in vivo, suggesting that they might be used as an RSV preventive and chemotherapeutic."

Such findings highlight the need to investigate the use of probenecid to prevent RSV infection in children aged 2 to 14, who have been given the medicine in combination with antibiotics and shown to be safe. To prove its effectiveness in vivo and with additional RSV strains, further research is needed.

The needed dose procedures and treatment length, as well as the drug's additional effects on cell communication and the inflammatory cascade due to the involvement of probenecid on pannexin 1 channels, must be determined.