A research consortium led by University Medicine Frankfurt has received follow-up funding of around one million euros from the Volkswagen Foundation. In total, the Volkswagen Foundation is funding four innovative projects on antiviral drug development with €4.2 million – in Frankfurt, Düsseldorf, Hamburg, and Saarland. The Fraunhofer Institute for Translational Medicine and Pharmacology ITMP is a consortium partner.

With MACROHEV, researchers aim to develop new active substances against the hepatitis E virus (HEV). They are pursuing two innovative and complementary approaches: small molecules that block a central mechanism of viral replication, and short RNA molecules that are specifically targeted against the virus. The funding builds directly on the results of the predecessor project MACROVIR. The upcoming project MACROHEV, funded with around one million euros, will run from 1 January 2027 to 31 December 2028.

For risk groups, a hepatitis E infection can become life-threatening

Hepatitis E is one of the most common viral liver infections worldwide. Many infections resolve on their own, but for certain patient groups the disease can take a severe course: Pregnant women in particular have an increased risk of acute liver failure, and people with weakened immune systems, such as after a transplant or during chemotherapy, can develop a chronic, difficult-to-treat infection. To date, a reliable antiviral therapy is lacking for these patients.

“Especially for patients with severe or chronic hepatitis E infections, we urgently need new therapeutic options. With MACROHEV, we are building on the findings and technologies of our predecessor project and specifically transferring them to the hepatitis E virus. Our goal is to develop active substances that effectively inhibit the virus while being well tolerated,” says Prof. Dr. Sandra Ciesek, study leader and director of the Institute for Medical Virology at University Medicine Frankfurt.

Two drug strategies targeting a central point of attack

At the focus of the researchers is the so-called macrodomain (also known as the X-domain) of the hepatitis E virus: an enzymatic module that is essential for viral replication and evasion of the immune response – and thus offers a promising target for new drugs. Already in the predecessor project MACROVIR, test systems and screening methods were developed that can be used to investigate viral macrodomains and test potential active substances for their antiviral effect. It became evident that a broad approach of a single drug against different viral macrodomains could not be implemented. MACROHEV therefore specifically targets the hepatitis E virus and utilizes new structural insights into its macrodomain.

“One approach uses structure-guided and fragment-based methods to search for small chemical molecules that bind to the macrodomain and inhibit its function. New high-resolution structural data will help us to identify and further develop drug candidates more precisely,” says Prof. Dr. Aimo Kannt, Head of Research Division at the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, whose teams in Frankfurt and Hamburg are contributing to the project.

In parallel, the team is pursuing a second, independent approach: siRNAs – short RNA molecules – are intended to specifically switch off the viral genetic information. The researchers aim to optimize these molecules so that they are taken up precisely by liver cells. Both strategies will subsequently be tested for their antiviral efficacy and tolerability in different liver cell models.

“The combination of two mechanistically independent approaches is a key advantage of MACROHEV. If we succeed in both blocking a crucial viral mechanism and specifically switching off the viral RNA, new possibilities will open up for an effective and, in the future, combinable therapy,” explains Prof. Dr. Sandra Ciesek.

A consortium uniting basic research and translational science

In addition to University Medicine Frankfurt, researchers from the University of Lübeck, the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Ruhr University Bochum, and the Institute for Pharmaceutical Chemistry at Goethe University Frankfurt are involved in MACROHEV. The industrial partner Dompé Farmaceutici is also on board, contributing compound libraries, bioinformatic methods, and expertise for the further development of drug candidates.

Building on the first funding phase, MACROHEV now aims to produce drug candidates suitable for further preclinical studies. In the long term, this could lead to new treatment options for people for whom no adequate targeted therapy is currently available. For University Medicine Frankfurt, the project is an example of how scientific findings can be developed step by step toward new medical applications.