Discovering the molecular footprint of a drug: how an anticancer drug can become a solution against multiple viruses

Currently, we do not have effective treatments for many viruses, and in numerous cases, the only option is to overcome them with our immune system. The need to develop new antivirals is a priority to combat known viruses but also to prepare for future threats.

Today, IrsiCaixa –a center jointly promoted by the ”la Caixa” Foundation and the Department of Health of the Generalitat of Catalonia– publishes in Nature Communications a study demonstrating the potential of plitidepsin, an anticancer drug developed by PharmaMar, to treat different viruses, including SARS-CoV-2, MERS, Zika, respiratory syncytial virus, hepatitis C, and herpes, among others.

The work involves several multidisciplinary research teams from the Animal Health Research Center of the Institute of Agrifood Research and Technology (IRTA-CReSA), the Josep Carreras Leukaemia Research Institute, and PharmaMar.

The versatility of this compound lies in its ability to modulate cellular functions beyond its primary point of action. By blocking its therapeutic target, plitidepsin triggers changes in other molecular processes that seem disconnected, generating a unique pattern that the research team defines as a "molecular footprint."

"Identifying the molecular footprint of a drug can reveal new applications beyond the known ones, allowing us to predict new uses and even avoid potential drug resistance," explains Nuria Izquierdo-Useros, Principal Investigator at IrsiCaixa.

From anticancer to antiviral

Plitidepsin blocks an essential process for the survival of cells and viruses: protein synthesis. “We wondered how cells could continue functioning after blocking such a crucial process,” comments Elisa Molina Molina, predoctoral researcher at IrsiCaixa.

The study reveals that cells compensate for this inhibition by activating alternative protein synthesis pathways, allowing them to survive. However, many viruses cannot exploit these alternative pathways, and as a result, their replication stops.

In the laboratory, plitidepsin has inhibited the replication of SARS-CoV-2, MERS, hepatitis C, Zika, herpes simplex, and respiratory syncytial virus at concentrations that do not affect the cells. However, some viruses, such as HIV, are able to use these alternative pathways, and thus the drug is not effective in stopping them.

This study also helps explain why plitidepsin regulates the production of certain proteins related to chronic inflammation, such as IL-6, as previously reported in articles. This feature, along with its antiviral role, has led to the initiation of a clinical trial for long COVID, led by the Fight Infections Foundation, where it could combat both the virus and the associated inflammation.

Regarding its role against COVID-19, preliminary clinical trial results suggest that plitidepsin reduces oxygen dependency in hospitalized patients by two days. This new work expands its potential use by demonstrating that plitidepsin can act against multiple viruses, opening the door to new therapeutic applications.

Drugs targeting human cells: key for future pandemics 

Most antivirals are designed to directly attack the virus. However, due to the rapid evolution of viruses and the emergence of variants, these treatments can become ineffective. Additionally, developing specific antivirals requires detailed knowledge of each virus, making it difficult to respond quickly to new pandemics. In contrast, drugs targeting human molecules do not have these limitations. Exploring the antiviral potential of these drugs through their molecular footprint offers a unique opportunity to discover new uses and applications.

For years, IrsiCaixa has been working on the creation and identification of broad-spectrum antivirals capable of acting against very different viruses. “Having a battery of safe drugs with antiviral potential against multiple viruses would allow us to respond quickly and effectively to future outbreaks, and even protect ourselves against unknown viruses,” emphasizes Izquierdo-Useros.