Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound coming from roots and seeds of Angelica archangelica (herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredient in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has showed previously strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures by using 34.5 and 69 µM doses. No dose related ICEP4 toxicity was seen on Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) and Natural Killer T (NKT) cells. No dose related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNFα release in cell supernatant. No survival rate decrease was observed neither on 24-hour acute nor 21-days chronic in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). Characteristic ICEP4 chemical compounding and its safe TTC let us to assume that an antiviral first-observed natural compound has been discovered. Potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe widely extended remedy, which may be ready-to-go for large-scale clinical trials under EMA emergency regulatory pathway. To the best of authors’ knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.
Competing Interest Statement
Dr. Iván José Galindo-Cardiel and Ezio Panzeri are co-authors of ICEP4-related patent application (GB2017123.7). Iratxe Uranga-Murillo is supported by a predoctoral contract from Aragón Government. Dr. Maykel Arias is supported by a Juan de la Cierva postdoctoral contract. Dr. Julian Pardo′;s laboratory is funded by FEDER (Fondo Europeo de Desarrollo Regional, Gobierno de Aragón -Group B29_17R-, Ministerio de Ciencia, Innovación e Universidades -MCNU-, Agencia Estatal de Investigación -SAF2017-83120-C2-1-R-), Instituto de Salud Carlos III, Fundacion Inocente Inocente, ASPANOA and Carrera de la Mujer de Monzón.
Footnotes
↵i Iratxe Uranga-Murillo is supported by a predoctoral contract from Aragón Government.
↵ii Dr. Maykel Arias is supported by a Juan de la Cierva postdoctoral contract.
↵iii Julian Pardo’s laboratory is funded by FEDER (Fondo Europeo de Desarrollo Regional, Gobierno de Aragón -Group B29_17R-, Ministerio de Ciencia, Innovación e Universidades - MCNU-, Agencia Estatal de Investigación -SAF2017-83120-C2-1-R-), Instituto de Salud Carlos III, Fundación Inocente Inocente, ASPANOA and Carrera de la Mujer de Monzón.