An adventure from a work in progress: Challenges and opportunities of pharmacophylogeny in combat against COVID-19 - PubMed (nih.gov) Phytother Res. 2023 Jan 27.

 doi: 10.1002/ptr.7736. Online ahead of print.

1 New situation, new challenges

The COVID-19 pandemic is not over yet. With the updating of national epidemic prevention policies, the variables have increased. Globally, the number of new weekly cases reported during the week of 12 to 18 December 2022 was over 3.7 million (WHO, 2022), with over 10,400 new fatalities reported. As of 18 December 2022, there were more than 649 million confirmed cases and over 6.6 million deaths reported worldwide. There are some circulating SARS-CoV-2 variants of concern, and numerous Omicron subvariants are under close monitoring (Doan et al., 2022). On the other hand, we have witnessed three years of China’s battle against the novel coronavirus; the country has extinguished over 100 outbreaks and successfully alleviated five waves of COVID-19 (China Daily, 2022). From Wuhan to Shanghai, and from the Delta variant to Omicron, China is tackling the qualms of pandemic. Chinese herbal medicines have always been at the forefront of the battle against SARS, influenza and COVID-19 over the years (Choi et al., 2020; Liu et al., 2012; Zhuang et al., 2022), which bear witness to the efforts and success in epidemic prevention and control.

With the recent optimization of COVID-19 countermeasures and the tuning of COVID-19 policies, China’s contest against the epidemic is entering a new chapter. As of January 8, 2023, the measures for the prevention and control of Class A infectious diseases stipulated in the law against novel coronavirus infection will be lifted (National Health Commission, 2022a), and COVID-19 is no longer included in the quarantine infectious disease management under the Frontier Health and Quarantine Law. However, the new spikes of infection pose great challenges against national health care systems, and solely relying on COVID-19 vaccines is far less enough in protecting immune-compromized population and reducing morbidity and mortality as much as possible. Herbal medicines could play an essential role in this respect (Huang and Li, 2022; Pagano, 2022). The National Administration of Traditional Chinese Medicine (TCM) and the administrative departments of TCM in provinces, regions and cities have successively issued documents such as TCM intervention guidelines and protection suggestions for the COVID-19 infected persons at home (National Administration of TCM, 2022), advocating that the health management and improving immunity can be conducted by means of herbal medicine prevention, air fumigation, epidemic prevention sachet, reasonable diet, fitness exercise, acupoint massage, regular daily living, etc.

2 Verified value of TCM during pandemic

In the process of fighting against COVID-19 in the past three years, TCM has played a very impressive role. For example, in the makeshift hospitals, both on-site-made and pre-made TCM decoctions were large-scale used to help mild and moderate patients recuperate (Li et al., 2020), which enabled them to get well quicker and have a lower rate of repeated infection. The TCM intervention is a boon not only in mainland China, but also in Taiwan Province and southeast Asia (Doan et al., 2022). When the Omicron variant of the virus struck the island in the spring of 2022, a locally made TCM formulation Qingguan No. 1 quickly became a hot commodity and then sold well abroad (Vinh Hoa Health, 2022). The cross-cultural communications are conducive to sharing experience and research so as to formulate more effective prescriptions.

In the clinical setting, usually there is a main TCM formula for the more common symptoms of COVID-19, and other formulas target various symptoms in different patients during the course of infection (Liu et al., 2020). For example, the bodies of some people are particularly painful, some have a very sore throat, and some others have a high fever. The treatment is fine-tuned in terms of diverse indications and some supporting formulas are tailored to each individual (National Health Commission, 2022b). On the other hand, different patients react differentially to the drugs. For instance, the gastrointestinal systems of some individuals are feeble and more sensitive to certain TCM ingredients; they might even vomit upon taking such ingredients. The TCM doctor can then modify the formula for optimal administration and efficacy. This is in line with TCM principle, i.e., personalized therapy for each patient, rather than same regime for all, for which more alternative medicinal materials have to be prepared. In this sense, pharmacophylogenetic studies can help bioprospecting more potentially useful medicinal taxa for flexible options (Gong et al., 2022).

3 Deepening insights into prevention and treatment of pandemic: Utility of pharmacophylogeny

Finding taxa phylogenetically connected to TCM species may be helpful in mining the blockbuster against COVID-19 (Zaman et al., 2020), which might mean putting researchers in the way of serendipity, but that is not only luck, and the uses of pharmacophylogeny do not end here. For instance, therapeutic effects of 7,451 TCM plants were grouped in 14 classes (Zaman et al., 2021), which were mapped onto the phylogenetic tree of 29,308 Chinese species to unearth hot nodes of therapeutic effects. The qualitative delineation of evolutionary distribution of pharmaceutical uses is being complemented by quantitative indices (Gaoue et al., 2021), so as to facilitate comparison and gain the holistic view. The phylogenetic reconstruction of species-level Tree of Life is challenging, which, however, showed its advantage in assessing likely uses of species rich orders/families in skin care and disease treatment, as clustering and scattering of skin efficacy of Ranunculales and Asteraceae plants were unambiguous on it (Hao et al., 2023). Scrutinizing the distribution of therapeutic efficacy on the phylogenetic tree will certainly afford clues for bioprospecting plants against COVID-19, while distribution patterns of plant specialized metabolites on the molecular phylogeny (Zhang et al., 2020) may also be useful in the search for natural compounds for antiviral and immune-modulatory purposes. Analogously, probing the distribution of compounds and efficacies of non-China plant species is also possible, as long as the more broadly inclusive plant phylogeny is constructed at the species level (Hu et al., 2020), from which intriguing cross-cultural comparison results would be revealed.

According to pharmacophylogeny, specific secondary metabolites are more likely to be identified in genetically closer species, and natural products in closely related taxa have higher similarity in molecular skeleton composition and the relationship of derivation (Liu et al., 2021). Such similarities of phytochemicals are manifested in the overall resemblance of biological activity or therapeutic effect in clinical application. Although a few polyphenols, cannabinoid compounds and alkaloids have been suggested as potential immunomodulatory and/or antiviral agents against COVID-19 (Pagano, 2022), their distribution on the molecular phylogeny is still elusive, let alone the structural subtypes of these compound groups. The rational utilization of pharmacophylogeny will help develop new medicinal plant species, avoid the blindness in traditional research methods and guarantee the targeted research. To this end, fully understanding the phytometabolites and chemodiversity of related taxonomic groups is requisite.

4 In the direction of the beginning: Traditional medicines illuminate post-pandemic era

Since the commencement of 21st century, there have been consecutive outbreaks of SARS, avian influenza, H1N1 flu, Ebola virus, and COVID-19 in the world, which have led to major losses of human life and property. Concurrently, diabetes, cancer, cardiovascular and cerebrovascular diseases, mental diseases and geriatric diseases have become more common worldwide. More worrisome is that COVID-19 will aggravate these basic diseases and lead to more deaths, especially in elderly. Coupled with the outbreak of major epidemics, these chronic diseases have posed a huge threat to human health and even survival. How to circumvent these threats? The ancient application and contemporary research of TCM and other traditional medicine systems give us a lot of spurs (Karimi et al., 2021; Pagano, 2022; Singh et al., 2021; Zhuang et al., 2022). The specialized phytometabolites induced by stress factors vary greatly, which, along with their therapeutic efficacy, may possess phylogenetic cues (Zaman et al., 2021; Zhang et al., 2020). After laying over phylogenetic background, the dominance of a specific type of phytometabolites, as well as allied efficacy, could be found in the specific part of phylogenetic tree, and the evolutionary trajectory of chemodiversity could be revealed, which has important guiding implication for the discovery and development of complementary/alternative phytomedicine resources. Such studies will improve the vitality of supply chain and sustain the development of herbal medicine industry.