Historical texts as a potential resource for plant-based antiviral agents against SARS-CoV-2 – the example of the Receptarium of Burkhard III von Hallwyl from 16th century Switzerland

Nina Vahekeni¹Jonas Stehlin¹Corinna Urmann^2,3Evelyn Wolfram¹Yannick Geissmann⁴Yelena Ruedin⁴Samuel Peter¹Olivier Engler⁴Andreas Lardos^1*

• ¹Natural Product Chemistry and Phytopharmacy Group, Competence Center for Drug Discovery, Institute of Chemistry and Biotechnology, ZHAW Zurich University of Applied Sciences, 8820 Waedenswil, Switzerland
• ²Organic-analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany
• ³TUM Campus Straubing for Biotechnology and Sustainability, Technical University of Munich, 94315 Straubing, Germany
• ⁴Spiez Laboratory, Federal Office for Civil Protection, 3700 Spiez, Switzerland

In search for effective prophylactic and possibly curative therapeutics against SARS-CoV-2, an historical-ethnopharmacological approach was used to select plants described in the Receptarium of Burkhard III von Hallwyl (RBH), a recipe text from 16th century Switzerland. Ten plant species were selected from the pre-established RBH database based on specific historical uses presumably linked with the treatment of viral infections. From each plant aqueous and hydroethanolic extracts were produced. CellTiter-Glo® Luminescent Cell Viability Assay was used to assess antiviral activity against SARS-CoV-2 and the effect on cell viability of the extracts. Of the ten plants tested, four displayed an antiviral activity ≥ 50% at 16.7 µg/ml with acceptable cell viability (> 75%): Artemisia vulgaris L. (aerial parts), Geranium robertianum L. (arial parts), Sambucus nigra L. (leaves) and Viola odorata L. (leaves). The crude extracts were partitioned in aqueous and organic pre-fractions and further analyzed. The ethyl acetate pre-fractions of G. robertianum, S. nigra, and V. odorata expressed significant antiviral activity of nearly 100% at 5.6 µg/ml (P < 0.05). The most potent inhibitory activity was observed for the ethyl acetate pre-fraction of the leaves of Viola odorata with 87% at 1.9 µg/ml (P < 0.0001). Alongside bioactivity testing, phytochemical fingerprints were made, with the aim to provide a preliminary characterization of the active crude extracts. An overview of published phytochemical and antiviral data on the four active plants reveals a fragmentary picture, especially when considering the plant parts investigated. Despite of the promising antiviral effects observed in our study, further in-depth pharmacological and phytochemical investigations are required to comprehensively evaluate the potential of our candidates. Our study suggests that an ethnopharmacological approach based on historical records of plant use in combination with a rational selection and testing procedure allows to identify interesting candidates, even among medicinal plants no longer in use. The process of selecting plants from RBH also illustrates the challenges associated with the study of historical texts, particularly the interpretation of the medicinal uses and the assessment of the botanical identities of historical plant names.