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The identification of antivirals that target different steps of the viral life cycle can serve as a starting point for the discovery of novel therapies and may contribute to a deeper understanding of the viral infectious cycle. The use of plants in traditional medicine spans centuries and encompasses a vast array of indications. Natural products derived from plant species continue to represent a significant reservoir of potential therapeutic agents. While natural compounds are not always employed as direct medicinal agents, they frequently serve as a source of inspiration for medicinal chemistry.
Our previous research on the search for natural antivirals against hepatitis C virus (HCV) provided proof of concept. Indeed, several plant molecules have been identified as potent antiviral agents against HCV, including EGCG, delphinidin, and dehydrojuncusol [1–3]. The latter, isolated from an extract of seagrass (Juncus maritimus), demonstrated a mechanism of action analogous to that of the anti-NS5A agent employed in hepatitis C treatment. However, dehydrojuncusol was not further developed, as the existing hepatitis C treatments were already highly efficacious.
Our subsequent research is now focused on human coronaviruses due to their potential for emergence, their pathogenicity, and the absence of efficacious antiviral agents. The objective is to identify antivirals with pan-coronavirus antiviral activity, defined as the capacity to inhibit multiple members of the human coronavirus family, in order to prepare for a potential future emergence. Our approach is a non-target approach, whereby the screening of pure natural compounds or plant extracts is conducted without a predicted mechanism of action or target. Once identified, the active plant extracts are subjected to "bioguided fractionation," a technique that involves the separation of molecules present in the plant according to their physicochemical characteristics, in order to isolate the active compound. The process comprises a number of stages, with the antiviral activity being evaluated at each stage, thereby justifying the term "bioguided." This is achieved through close collaboration with members of the Pharmacognosy team of BioEcoAgro Joint Research Unit 1158 (Lille, directed by Sevser Sahpaz), Céline Rivière, Simon Bordage, and Vincent Roumy. For each newly identified antiviral, the mechanism of action is determined, if feasible. By screening a multitude of natural compounds, it is our objective to identify effective antivirals with original mechanisms of action, thereby providing the foundation for future treatments against coronaviruses.
For illustrative purposes, a selection of recent results is provided below
Following antiviral screening of plant extracts from Côte d'Ivoire and bioguided fractionation (collaboration Université Nangui Abrogoua, Abidjan, and BioEcoAgro), a highly active inhibitor of coronaviruses was isolated [4]. This compound, designated pheophorbide a (Pba), is a breakdown product of chlorophyll and functions as a photosensitizer. The mechanism of action was investigated, and the results demonstrated that the antiviral activity of Pba is dependent on light activation. By cryo-electron microscopy (in collaboration with CBMN UMR 5248, Bordeaux), it was demonstrated that Pba induces a rigidification of the viral envelope. Pba represents a novel natural antiviral agent against SARS-CoV-2 with direct photosensitive virucidal activity, offering a promising approach for disinfection of surfaces contaminated with SARS-CoV-2 or other coronaviruses.
The team's research continued in collaboration with the BioEcoAgro laboratory, with a focus on coastal plants in the Hauts-de-France region that thrive in saline soils. These plant species, known as halophytes, have developed the ability to synthesize specific molecules that enable them to survive in this unique environment. Twenty-five extracts derived from halophytic plants native to the Hauts-de-France coastline were subjected to an antiviral screening assay against the HCoV-229E coronavirus [5]. The sea buckthorn extract (Hippophae rhamnoides, Figure 2) was identified as the most promising candidate. Following bioguided fractionation, the active compounds were isolated, among which the cinnamoyl oleanolic acids appear to be the most promising. Indeed, the extracts were observed to inhibit the in vitro infection of both SARS-CoV-2 and HCoV-229E. This work is still in its exploratory phase, with numerous experiments yet to be conducted, particularly aimed at elucidating the mechanisms of action of these antiviral agents.
The team's research interests extend beyond plant extracts to encompass pure natural compounds. An antiviral screening of dozens of pure plant natural compounds revealed that nhyperforin, the major compound from St. John's wort extract (Hypericum perforatum), demonstrated antiviral activity against HCoV-229E [6]. Moreover, hyperforin has been shown to possess pan-coronavirus antiviral activity against both highly virulent and mild human coronaviruses. Additionally, hyperforin has been demonstrated to be active during the replication step and in primary human airway epithelial cells. In light of the existing data on the bioavailability and safety of St. John's wort compounds, the results provide a promising avenue for the treatment of coronavirus infections within a pandemic preparedness strategy. The project will proceed with an investigation into the mechanism of action of hyperforin.
