From Bacteria to Insects: New Approaches Against Influenza Viruses

Seasonal flu is worldwide one of the most important respiratory diseases. Every year millions of people become seriously ill, hundreds of thousands die. A problem: influenza viruses mutate rapidly. Therefore, vaccines must be updated regularly, and the viruses already develop resistances to existing drugs. A promising approach involves targeting host factors – human proteins - which significantly reduces the development of resistance.

At Fraunhofer IME, a platform has been developed to rapidly identify antiviral molecules from complex mixtures. Using this UHPLC-UHR-MS/MS pipeline, extracts from bacteria, fungi, or insects are first tested in the lab for antiviral activity. Then the active samples are separated into many small fractions and chemically “scanned” with high-resolution mass spectrometry. This allows the antiviral effect to be traced step by step back to individual molecules - known natural products are identified and new substances can be targeted for further study.

How well this works was shown by analyzing extracts from a marine bacterium (Tistrella mobilis): the pipeline reliably identified the known natural product didemnin B, which acted strongly against various influenza viruses.

Another focus was on natural products from insects. In the hemolymph, the blood-like body fluid of larvae of the greater wax moth (Galleria mellonella), a peptide was discovered and identified as “Inducible Serine Protease Inhibitor 2” (ISPI-2). ISPI-2 blocks a human protein (TMPRSS2) that influenza viruses need for replication. In cell culture, ISPI-2 markedly inhibited the replication of an H1N1 virus and was also effective in human lung cells. In combination with the approved flu drug Oseltamivir, the antiviral effect was enhanced.

The results show: the new pipeline is a powerful tool to harvest promising lead structures from diverse bioresources - from bacteria and fungi to insects. It enables discovery of known effective molecules as well as identification of new host-directed candidates like ISPI-2. Therefore, it makes an important contribution to the development of future flu therapies with novel mechanisms.