Broad-spectrum antiviral compounds discovered

An interdisciplinary research team has identified two antiviral drug candidates effective against a wide range of viruses. The study demonstrates how combining computer-aided modeling with laboratory validation can speed up the development of new antiviral drugs.

The researchers used computer simulations to search for specific metabolic processes necessary for viral reproduction but not vital for the cell itself. Using this method, the team identified two active agents that successfully combated various viruses in initial laboratory tests. The study was published in Communications Biology.

Using data from virus-infected tissues, the international research team developed computer models representing the complex metabolism of cells.

The team then used these tissue-specific models to simulate the replication of various RNA viruses, which are of particular importance due to their pandemic potential. The modeling revealed metabolic processes that the viruses require for replication but that are not essential for cellular survival.

Using these models, the researchers have predicted specific metabolic pathways essential for viral replication, which represent potential targets for antiviral therapies.

They then searched existing drug databases for substances that inhibit precisely these metabolic processes.

Since most viruses have similar basic replication requirements, the international research team from Germany, France, Italy, Greece, and Australia suspected that this strategy could be used to inhibit a wide variety of viruses.

They  tested this hypothesis experimentally and found various substances with broad antiviral activity against very different virus families.

Infection experiments in cell cultures confirmed that two drug candidates—phenformin and atpenin A5—effectively inhibit viral replication.

Phenformin interferes with the metabolism of the cell and was therefore previously used as a drug in type 2 diabetes. Since phenformin is well-characterized for use in humans, their findings could be used to establish supportive therapy against corona or flavivirus infections in the relatively short term.

Part 1

In animal experiments with SARS‑CoV‑2‑infected hamsters, phenformin significantly reduced the viral load in the respiratory tract. In cell cultures, phenformin also inhibited the multiplication of dengue viruses, for which there is currently no approved treatment.

Extensive clinical studies on the use of phenformin as an antidiabetic agent have already established its safety in humans. Further clinical studies are needed to determine if phenformin has an antiviral effect in humans. In contrast, atpenin A5 is an experimental substance that demonstrates the feasibility of the methodological approach in cell culture.

Further studies must be conducted to determine whether variants of the substance can be used in animal models where they are both tolerated and have an antiviral effect.

According to the scientists, the developed methods and identified drug candidates are an important step in the rapid development of potential treatments for future pandemics.

Alina Renz et al, Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses, Communications Biology (2025). DOI: 10.1038/s42003-025-08148-y

Part 2

Depriving mice of iron can increase the chance of intersex offspring

Iron deficiency in pregnant mice may lead to the development of ovaries in a small proportion of offspring carrying XY chromosomes, which typically determine male sex. The findings, published in Nature this week, reveal a link between iron metabolism and sex determination in mammals.

A key gene responsible for male sex determination in mammals is Sry, which controls the development of the testes and is found on the Y chromosome. An enzyme called KDM3A that is essential for regulating Sry gene expression is known to rely on Fe²⁺ for its activity. However, how iron levels may influence sex determination remains unclear.

To explore the potential connection between iron metabolism and sex determination in mammals,  researchers conducted a series of experiments using cultured cells and mice. They found that genes favoring accumulation of Fe²⁺ are upregulated in developing mouse embryonic gonads during the crucial period of sex determination.

When the researchers reduced iron levels in cultured cells to approximately 40% of normal levels, expression of the Sry gene was largely suppressed, and the XY gonads began to show genetic markers associated with ovary development.

The researchers then tested the effects of both short-term and long-term iron deficiency in pregnant mice. Short-term iron deficiency was induced by administering an iron-removing drug to pregnant mice for about five days around the time of embryonic sex determination. Among 72 XY offspring born to these mothers, four developed two ovaries and one developed an ovary and a testis. Long-term iron deficiency was induced through a low-iron diet starting four weeks before pregnancy and continuing for six weeks.

This long-term low-iron diet showed no effect on sex determination until a loss-of-function mutation in the gene that encodes KDM3A was introduced in the mothers. This resulted in male-to-female sex reversal in two of 43 XY offspring. No abnormalities were observed in offspring born to mothers with normal iron levels in either of the experiments.

The findings demonstrate a key role of iron in mammalian sex determination, although the effects of iron deficiency on human pregnancies were not investigated.

 Makoto Tachibana, Maternal iron deficiency causes male-to-female sex reversal in mouse embryos, Nature (2025). DOI: 10.1038/s41586-025-09063-2. www.nature.com/articles/s41586-025-09063-2

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