Keywords
Mpox - monkeypox virus - phytotherapy - evidence gaps - herbal medicine - natural product
Introduction
Monkeypox virus, an enveloped double-stranded DNA virus belonging to the Orthopoxvirus genus within the Poxviridae family, is the causative agent of Mpox. Initially discovered in monkeys in Denmark in 1958, the first recorded case in humans occurred in the Democratic Republic of the Congo in 1970. This neglected infectious disease culminated in a pandemic between 2022 and 2023, resulting in 85,473 cases and 89 mortalities in 110 countries [1]. Fifteen months after the conclusion of this emergency period, the World Health Organization declared Mpox a ʼpublic health emergency of international concernʼ on 14 August 2024, in response to the circulation of a newer and more virulent strain designated as clade 1b [2]. This new declaration came amidst concerning trends in several regions, including some endemic areas. For instance, the Democratic Republic of the Congo reported a high number of cases, including an annual incidence
of 1146 per 100,000 in 2023 and continued high case numbers in 2024 [3], [4].
The transmission of Mpox was suggested to be from zoonotic sources and contact with infected animals, but it is postulated that the new clade is spreading via sexual contact [5]. This disease may lead to dermatologic, inflammatory, respiratory, ophthalmic, respiratory, or gastrointestinal complications, especially in patients with weak immune systems, a condition that may be prevalent in affected populations [6], [7]. In settings with limited resources where vaccines are unavailable, early intervention and supportive care are vital for alleviating symptoms like pain and rash and preventing complications in Mpox patients. The public health risk of resistant strains, such as clade 1b, underscores the need for ongoing treatment exploration [8]. Phytotherapy and natural products, with their long history of managing symptoms and demonstrating anti-infective efficacy,
could be beneficial in these challenging situations [9].
A preliminary search of the PubMed database retrieved no studies specifically addressing natural compounds for the management of Mpox (see supplementary material, preliminary search). Therefore, this novel study aimed to systematically investigate the literature for natural compounds with potential efficacy against Mpox or its associated symptoms.
Results
A total of 37 articles, encompassing 242 citations, were retrieved (see supplementary material, Figure 1S and Table 1S). The first study was published in 2011. Since then, the net number of publications and citations has steadily increased, with 2023 recording the most citations (n = 114) and publications (n = 21) (see supplementary material, Figure 2S).
According to the World Health Organizationʼs regional classifications, researchers from the South-East Asian and Eastern Mediterranean Regions contributed the majority of studies in this field, with Saudi Arabia, India, and China leading in terms of international collaborations. Notably, nearly all institutions had a single publication, indicating diverse contributions from various entities. Whilst several studies reported no funding, others received support from a range of sources, particularly from the authorsʼ institutions.
All studies were at the preclinical stage, with in silico investigations comprising the majority. Additionally, there were four in vitro studies, with only one conducted after the 2022 Mpox pandemic. The literature revealed no in vivo or clinical interventions regarding phytotherapy or the utilisation of natural compounds in the management of Mpox.
The predominant focus of the literature was on phytotherapy. Among the lead phytochemicals identified, polyphenols, encompassing both aglycones and glycosides, were the most prevalent, with quercetin, rutin, and kaempferol cited as the most frequently mentioned compounds. Other notable classes included alkaloids, terpenoids, and tannins, each represented by at least one compound with a solitary occurrence. Additionally, natural bacteriocins, specifically glycocin F and lactococcin G, were reported. In terms of the mechanisms studied, most compounds exhibited effects on profilin-like protein, particularly the A42R protein, followed by thymidine kinase and DNA-dependent RNA polymerase of the monkeypox virus. Further details can be found in the supplementary material, Table 2S.
From an initial set of 823 author-provided and index keywords, a refined subset of 26 keywords was identified, each with a minimum occurrence of 5 in the literature. By removing redundant keywords, a graph was generated that illuminates the dominance of molecular docking and its correlation with keywords such as monkeypox, natural product, antiviral agent, and unclassified drugs. This graph further emphasised the preclinical focus of the literature pertaining to natural compounds as a potential treatment for Mpox (see supplementary file, Figure 3S).
Discussion
This study constitutes the first comprehensive examination of the literature regarding natural compounds with potential efficacy against Mpox via a systematic approach. The findings indicate a predominant emphasis on molecular docking studies of phytochemicals, particularly flavonoids and alkaloids, alongside reports of the potential efficacy of microbial-derived natural compounds against Mpox. However, there remains a notable scarcity of in vitro investigations and a complete absence of in vivo or clinical studies within the current research landscape.
Translational research is necessary to introduce findings from basic science to practical applications in the clinical practice [10]. However, the literature appears to have reached a saturation point regarding in silico investigations aimed at identifying natural lead compounds effective against Mpox, underscoring the necessity for further evaluation of these compounds through laboratory and animal studies as the next logical step. Whilst the biohazard nature of Mpox presents significant challenges for laboratory research, future investigations should prioritise study designs that could facilitate critical translation points in clinical medicine. Such endeavours are essential for advancing promising compounds from the laboratory bench to the bedside, enhancing patient care and therapeutic outcomes. Otherwise, the research landscape risks becoming inundated with numerous natural compounds, with only a select few undergoing practical
investigations against this global threat.
Materials and Methods
A comprehensive search was conducted across PubMed, Scopus, and the Cochrane Database of Systematic Reviews from inception until 26 August 2024, utilising an exhaustive list of keywords related to ‘Mpoxʼ, ‘herbal medicineʼ, and ‘natural compoundsʼ. Additionally, preprints were obtained through the Scopus database. No filters were applied, allowing studies in all languages to be considered eligible for inclusion. Studies lacking original data, such as narrative reviews with no clear methodology, those focused on vaccine development, or those addressing epidemiological and surveillance systems were excluded from the analysis. Furthermore, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for relevant studies. All identified studies and literature from these databases were collated into a single file using Microsoft Excel Version 2108. The data were analysed for publication and citation trends, compounds or
herbal plants investigated, the effects of these compounds on the Mpox virus, associated keywords, and basic characteristics, including author names, publication years, funding sources, and study designs. Data visualisation techniques were performed using Microsoft Excel and VOSviewer software version 1.6.20 (Leiden University, Leiden, Netherlands).
Contributorsʼ Statement
A. Sharifan: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing – Original Draft, Writing – Review & Editing, Visualization, Supervision, Project administration.
