Two classes of natural substances with efficacy against RNA viruses discovered

The COVID-19 pandemic triggered by SARS-CoV-2 has challenged healthcare systems around the world in an unprecedented way. The rapid global spread of this pathogen, combined with sometimes severe disease progression, shows how urgently effective drugs are needed to treat viral diseases. However, SARS-CoV-2 is by no means the only human pathogenic RNA virus with high economic and social relevance. Therefore, the identification of new active substances with broad efficacy against emerging viral pathogens is of great importance, especially with regard to possible viral pandemics in the future. Rolf Müller's team at HIPS has been successfully researching antibacterial natural substances isolated from soil bacteria for many years. In particular, actinobacteria, which have been used for decades, and myxobacteria, which have been much less researched to date, are valuable sources of new natural products. The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.

The researchers have now succeeded in isolating two families of active substances with antiviral activity from the bacteria: Persicamidine and Thiamyxine. While the persicamidines were isolated from a newly discovered strain of actinobacteria, the thiamyxins originate from a strain of myxobacteria found by HIPS scientists in the immediate vicinity of the institute. As part of the citizen science project „The Microbial Treasure Chest“, the HIPS strain collection has already been expanded by around 1000 new myxobacteria, which have been isolated from more than 700 soil samples submitted to date (for more information, see: www.hips.saarland/sample/).

Both of the above-mentioned bacterial families are well-known producers of natural products, especially antibiotics. In the studies that have now been published, the scientists at HIPS, in cooperation with the virus specialists from the working groups of Prof Dr Thomas Pietschmann at TWINCORE and Prof Dr Ralf Bartenschlager at the DKFZ, used their many years of experience and expertise in the field of antibiotics research to isolate the new natural products and investigate their antiviral efficacy in greater detail.

Both natural product families show structural peculiarities, which made extensive structural analyses necessary in the case of persicamidines. For the thiamyxins, it was also possible to describe a biosynthesis model using so-called folding experiments with specially labelled precursor substances. For both newly discovered natural product families, the researchers were able to demonstrate strong inhibition of RNA viruses in coronavirus, Zika virus and dengue virus infection models. In the case of persicamidines, the activities against SARS-CoV-2 and hCoV-229E are even roughly comparable with the conditionally approved drug Remdesivir, which is used for the treatment of COVID-19.

 „The problem of antimicrobial resistance and the search for new antibiotics are the real core of our research. However, the COVID-19 pandemic has reminded us how important the development of antiviral agents is. That is why we want to use our expertise to develop active substances against both bacterial and viral infections in the future. In the case of persicamidines, we can see that in some cases the source of the solution to global problems even lies right on our doorstep," says Prof. Dr Rolf Muller, Managing Director of HIPS and Head of the Department of Microbial Natural Products and Coordinator of the New Antibiotics research area at the German Centre for Infection Research (DZIF).

Due to their good antiviral activities, the new natural product classes represent promising starting points for the development of potential active substances against SARS-CoV-2 and other RNA viruses. Due to the comparatively low production rates of thiamyxins, biotechnological optimisation of production or the development of a chemical synthesis route are now of great interest in order to make the natural substance available in sufficient quantities for further analyses. In follow-up studies, the researchers want to investigate the mechanisms of action of the two new natural product families, the elucidation of which will be a further step towards the development of antiviral agents.

Article of "LABO" from 20.03.2023