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 ‘Mpox’, ‘herbal medicine’, and ‘natural compounds’. 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.
