In the current state of knowledge, the drug therapy available for the treatment of COVID-19 disease is based on some anti-inflammatory drugs and monoclonal antibodies such as anakinra, baricitinib, sarilumab e tocilizumab. Mostly these are drugs admitted limited to the treatment of adults hospitalized with moderate/severe COVID-19 pneumonia, or in high flow oxygen therapy or non-invasive mechanical ventilation, or with high levels of systemic inflammation indices (for more details see please visit the website of the Italian Medicines Agency).

To these could be added the latest antiviral drugs molnupiravir and paxlovid still awaiting authorization in our country. In the field of natural substances, recent studies have highlighted the efficacy of some phytochemical compounds against the SARS-CoV-2 virus, in particular the phenyl propanoid compounds quercetin and eugenol, widely spread in the plant world. These are mostly in silico studies or clinical trials in which quercetin was administered as adjuvant therapy combined with conventional therapy in non-hospitalized patients with non-severe symptoms of COVID-19 (Di Pierro et al., 2021a, b; Paidi et al., 2021; Rizzuti et al., 2021).

In this context, the Phytochem Lab recently published a work, the result of an international collaboration, in which two natural substances were tested in silico against the SARS-CoV-2 virus. These are tomatidine, a steroid alkaloid, and patchoulol, a sesquiterpene isoprenoid. As is known, in silico methods are based on computer simulations and computational analyses, such as molecular docking, capable of predicting the link between a low molecular weight molecule, a possible drug, and a target protein, with the advantage of not requiring in vivo tests on animal models. In this study it was shown that the two substances and in particular tomatidine bind stably to the active site of target proteins such as 3CLpro, NSP15 and human COX-2, preventing them from functioning properly.

The SARS-CoV-2 virus genome consists of single-stranded RNA of positive polarity that encodes 29 proteins. In particular, the 3CLpro protein is the main protease used by SARS-CoV-2 for its replication and whose inhibition is lethal for the virus itself. Inhibition of COX-2 cyclooxygenase is also important for blocking the inflammatory cascade that characterizes COVID-19 disease. Finally, in silico simulations demonstrated that tomatidine and patchoulol have high absorption and bioavailability and are free from toxic effects. The results of this study are very relevant because many research groups are working on 3CLpro as a possible drug target, being strongly conserved in all types of coronaviruses (Zrieq et al., 2021).

– Di Pierro, F., Iqtadar, S., Khan, A., Mumtaz, S. U., Chaudhry, M. M., Bertuccioli, A., … & Khan, S. (2021a). Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial. International Journal of General Medicine, 14, 2807.

– Di Pierro, F., Derosa, G., Maffioli, P., Bertuccioli, A., Togni, S., Riva, A., … & Ahmed, S. (2021b). Possibl Therapeutic Effects of Adjuvant Quercetin Supplementation Against Early-Stage COVID-19 Infection: A Prospective, Randomized, Controlled, and Open-Label Study. International Journal of General Medicine, 14, 2359.

– Paidi, R. K., Jana, M., Raha, S., McKay, M., Sheinin, M., Mishra, R. K., & Pahan, K. (2021). Eugenol, a Component of Holy Basil (Tulsi) and Common Spice Clove, Inhibits the Interaction Between SARS-CoV-2 Spike S1 and ACE2 to Induce Therapeutic Responses. Journal of Neuroimmune Pharmacology, 1-13. –

– Rizzuti, B., Ceballos-Laita, L., Ortega-Alarcon, D., Jimenez-Alesanco, A., Vega, S., Grande, F., … & Velazquez-Campoy, A. (2021). Sub-micromolar inhibition of SARS-CoV-2 3CLpro by natural compounds. Pharmaceuticals, 14(9), 892.

– Zrieq, R.; Ahmad, I.; Snoussi, M.; Noumi, E.; Iriti, M.; Algahtani, F.D.; Patel, H.; Saeed, M.; Tasleem, M.; Sulaiman, S.; Aouadi, K.; Kadri, A. Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations. Int. J. Mol. Sci. 2021, 22, 10693.