Molecular dissection of natural product actions as antivirals against respiratory viruses

Infections with common respiratory viruses such as influenza viruses (IV), coronaviruses, or respiratory syncytial virus (RSV) are still a major challenge to our health care system. Currently licensed antiviral drugs to these pathogens if existing at all are often only effective in early stages of infection and are often poorly active in severely diseased patients. Furthermore, usage of direct-acting antivirals targeting distinct viral protein structures comes with the ultimate drawback of resistance development and might not be suited to new variants or emerging viruses. A final shortcoming are adverse side effects that may occur with small molecule drugs. Thus, new antiviral approaches with a broad activity and safety as well as a high barrier for development of resistance are urgently needed. Our research goal since years is to foster the development of broadly acting antiviral approaches on the basis of natural plant extracts that are safe and already in clinical use for other indications. In the past years, we have identified antiviral activity of different plant derived natural products against several viral pathogens. Most recently, we showed that extracts from Hypericum perforatum and its active ingredients Hypericin and Pseudohypericin display strong antiviral activity against SARS-CoV-2. First preliminary results indicate activity also against other enveloped viruses, while non-enveloped viruses appear to be unaffected. With regard to the molecular mode of action (MoA), data from us and others indicate, that components of the extract may directly interact with the virus membrane envelope to exert antiviral action. Therefore, we hypothesize, that the extract or its ingredients may act broadly against multiple enveloped viruses and that resistance development is highly unlikely because of the missing molecular interaction with defined viral protein structures. We have installed a research program to test the broad antiviral action and safety of Hypericum perforatum extract and its ingredients Hypericin and Pseudohypericin using different IV, corona viruses and RSV to cover relevant enveloped respiratory viruses. In addition, details on the molecular MoA are under investigation by different ultra-high resolution microscopic approaches since this knowledge is crucial for further clinical development.