Mpox (formerly monkeypox): pathogenesis, prevention, and treatment

Abstract

In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions. The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus. Consequently, nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination. Nevertheless, the available therapeutic options for Mpox virus infection remain limited. So far, only a few numbers of antiviral compounds have been approved by regulatory authorities. Given the high mutability of the Mpox virus, certain mutant strains have shown resistance to existing pharmaceutical interventions. This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism. Currently, there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox. To address this issue, we conducted a review covering the physiological and pathological processes of Mpox infection, summarizing the latest progress of anti-Mpox drugs. Our analysis encompasses approved drugs currently employed in clinical settings, as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox. Furthermore, we have gained valuable insights from the process of Mpox drug development, including strategies for repurposing drugs, the discovery of drug targets driven by artificial intelligence, and preclinical drug development. The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox.

Fig. 1

The timeline of the historical review and major milestones in Mpox

Fig. 2

The epidemiological characteristics, pathogenesis, clinical diagnosis, and treatment of Mpox. a The transmission of Mpox occurs through animal-to-animal, animal-to-human, and human-to-human routes. b Clinical symptoms typically manifest after Mpox infection. c Symptoms of Mpox infection may vary based on the immune status and clinical treatment options and clinical treatment options are listed

Fig. 3

The genome structure and potential antiviral targets of Mpox virus. The Mpox virus genome consists of a double-stranded linear DNA comprising approximately 196,858 base pairs. It consists of a central recognition region, two variable region, and two terminal inverted terminal repeats (ITRs) (Monkeypox virus strain Zaire, GenBank accession number: AF380138.1, web link: https://www.ncbi.nlm.nih.gov/nuccore/17529780). In the genome map, target genes implicated in the interaction between Mpox virus and antiviral drugs are listed. Most essential genes are located in the central region of the genome

Fig. 4

The life cycle of Mpox virus replication in hosts and potential targets for anti-Mpox virus drugs. The complete life cycle of Mpox virus infection: from entry into host cells to excretion. Briefly, both EEV and IMV viral particles penetrate the host membrane through membrane fusion and endocytosis. Mpox virus viral particles utilize glycosaminoglycans as host receptor. IMV particles enter the cytoplasm and are transported to the perinuclear replication factory via microtubules. The released Mpox virus genome serves as a template for DNA replication. Furthermore, IMV are enveloped by the Golgi apparatus to form IEV, and are transported to the cell surface via actin or microtubules. Part of the important drugs targeting each stage of the replication process are listed. EEV extracellular enveloped virions, IMV intracellular mature virions, IEV intracellular enveloped virions, IV immature virion

Fig. 5

The host cell immune response after Mpox virus infection. The Mpox induces specific and non-specific immune responses after infection. Briefly, upon entry of Mpox virus into host cells, mononuclear phagocytes and neutrophils initiate recruitment and increased proliferative infiltration, other antigen-presenting cells (such as dendritic cell) become activated, leading to the release of effector molecules and chemokines, while other cells (T cells, B cells, NK cells and the complement system) of the immune system also begin to exert their corresponding effector functions. IL interleukin, Th helper T cell, IFN Interferon, ADCC antibody-dependent cell-mediated cytotoxicity

Fig. 6

Illustrates the signaling pathways associated with the targeted actions of certain drugs following Mpox virus infection. Upon infection, Mpox inhibits pyroptosis, impeding the formation of inflammasomes and activation of caspase-1. This blockade prevents pyroptosis and hampers the adequate activation of the immune response against Mpox infection. However, nigericin, an activator of NLRP3 can induce pyroptosis in host cells, making it a promising candidate for an anti-Mpox drug. Moreover, tBID, a protein involved in apoptosis, is suppressed upon Mpox virus infection, thereby inhibiting both intrinsic and extrinsic apoptotic pathways and ensuring the survival of Mpox virus within host cells. This mechanism can be exploited by employing apoptosis inducers as a strategy to combat Mpox virus. Furthermore, Mpox virus infection triggers the binding of EGF and EGFR, activation downstream MAPK and MEK signaling pathways, leading to the release of inflammatory and chemotactic factors, and modulation of immune cells. That is, EGFR inhibitors like gefitinib may exhibit significant anti-Mpox activity