Enterovirus (EV)

What is Enterovirus (EV)?

Enterovirus (EV) is a small, non-enveloped, single-stranded RNA virus that predominantly lives in the intestine. These viruses are infected and transmitted through the digestive tract, mainly poliovirus, coxsackievirus, echovirus and novel enteroviruses, and more than 70 serotypes have been identified. Enteroviruses belong to a large genus that contains many different pathogens that can cause a variety of diseases in humans. In the small RNA virus family, hepatitis A virus (hepatovirus) and poliovirus (enterovirus) are the only human pathogens that require an effective vaccine. Efforts to develop enterovirus inhibitors are currently still limited to human rhinoviruses.

Replication mechanisms of EV infection

The infection cycle of enteroviruses involves multiple steps. After cell entry and virion uncoating, the monocistron RNA of the virus acts as mRNA, directing the synthesis of most proteins. Proteolytic processing of polyproteins leads to the release and activation of proteins involved in viral RNA replication. Replication of viral positive-strand RNA begins with the synthesis of complementary negative-strand RNA in the cytoplasm by RNA-dependent RNA polymerase (RdRp)3D. Negative-strand RNA is used as a template to generate new positive-strand RNA molecules. RNA synthesis occurs in virus-induced replication complexes on the outer surface of membrane vesicles. Once newly synthesized RNA is released from the replication complex, it can enter another round of translation and replication, or it can be packaged as a capsid protein to form infectious viral particles. Lysis of the host cell leads to the release of viral progeny.

Viral RNA replication is dependent on the help of other viruses and host proteins. The initiation of negative strand synthesis requires the placement of RdRp near the 3' end of the positive strand, while the enzyme should be placed at the 3' end of the negative strand to initiate the synthesis of the positive strand. Since the 3' ends of the complementary strand are different, the replication mechanism identifies two different types of origin of replication, called oriL and oriR, respectively, to initiate the synthesis of the positive and negative strands.

Enterovirus classification

Traditional taxonomic and subpopulation identification criteria for enteroviruses are based on how the virus replicates in cells, the clinical syndromes or diseases caused, and the manifestation of disease in suckling mouse models. Enteroviruses can be divided into poliovirus (PV), coxsackievirus A (CVA), coxsackievirus B (CVB), echovirus (E) and novel enteroviruses. Novel enteroviruses have been isolated since 1969, such as novel enterovirus type 71 (EV71). With the development of molecular sequencing, the International Committee on Virus Taxonomy has reclassified enteroviruses according to their biological and genetic characteristics, and divided them into enteroviruses group A, group B, group C, and group D. According to molecular phylogenetic analysis, the classification criteria of enteroviruses were redefined, and the enteroviruses could be divided into 12 groups, with groups A-D and E-J (group I, camel enterovirus). Human enterovirus groups A, B, C, and D, with more than 100 serotypes. In recent years, rhinovirus has been classified as enterovirus, including groups A, B, and C, and more than 140 serotypes have been isolated.

Fig.1 Taxonomy of Enteroviruses. (Nikonov O. S., et al., 2017)

Enterovirus associated diseases

Respiratory tract infections: Human rhinoviruses are the main causative agent of the common cold and also belong to the enterovirus family. Although infections are usually mild, in some cases, especially for people with weakened immunity, can lead to severe lower respiratory tract infections.

Enterovirus meningitis: Enterovirus meningitis is an inflammation of the meninges caused by enteroviruses that typically presents with fever, headache, neck stiffness, and light sensitivity. Although most cases are self-limited and have a good prognosis, they can lead to serious complications in some high-risk populations that require hospitalization and close monitoring.

Polio: Caused by the poliovirus, it can cause severe neurological damage and paralysis. Despite widespread vaccination worldwide, sporadic cases are still occurring in some areas.

Neonatal infections: Newborns are particularly susceptible to enteroviruses, which can lead to serious multisystem disease, including damage to the heart, liver, and brain.

Enterovirus treatment

The treatment of enterovirus infection is mainly concentrated in two categories: antiviral drugs and immunomodulatory drugs.

Antiviral therapy

Pleconaril: An antiviral drug that works primarily by inhibiting the binding of the virus to the host cell and preventing the release of viral RNA. It targets a conserved hydrophobic pocket of a major viral capsid protein called VP-1. By binding to the VP-1 protein, which is an important component of many viruses, Pleconaril stabilizes the viral capsid structure, thereby preventing virus attachment to the host cell surface and detachment of the viral coating. This mechanism effectively blocks the infection process of the virus, so that it cannot invade the host cell and replicate, so as to achieve the antiviral effect.

Ribavirin: A guanosine (ribonucleic acid) analogue that acts as a viral inhibitor by blocking viral RNA synthesis and capping viral mRNA. As a broad-spectrum antiviral, ribavirin is effective against a variety of RNA viruses, including certain enteroviruses. After ribavirin enters the cell, it is converted into its active form by intracellular enzymes, interfering with the replication process of the virus. Specifically, ribavirin is able to inhibit RNA-dependent RNA polymerase, thereby preventing the synthesis of viral RNA. At the same time, ribavirin can also affect the capping process of viral mRNA, making the viral mRNA unstable and unable to perform normal translation, which ultimately leads to the inactivation of the virus.

Favipiravir: A novel antiviral drug that has been shown to be effective against enteroviruses in several in vitro studies. It prevents viral replication by inhibiting viral RNA-dependent RNA polymerase. Preclinical studies have shown that Favipiravir is effective in inhibiting the replication of a variety of RNA viruses, including some strains of viruses that are resistant to other antiviral drugs. Currently, clinical trials on the efficacy and safety of Favipiravir against EV infection are still ongoing. These trials are designed to further evaluate its antiviral efficacy and potential adverse effects in humans to determine its feasibility in clinical treatment.

Immunoregulatory therapy

Interferon: Interferon is a protein with broad-spectrum antiviral activity. It inhibits the replication of the virus by enhancing the response of the host's immune system. Although it has been shown to be effective against enteroviruses in some studies, its clinical application is limited by side effects.

Intravenous immunoglobulin (IVIG): It used to treat severe EV infections, especially in immunocompromised patients. IVIG contains high levels of antibodies that neutralize the virus, providing passive immunity.

BOC Sciences is committed to providing high-quality scientific tools and compounds for enterovirus research. They provide a variety of antiviral drugs, immunomodulators and other related scientific research reagents to help researchers conduct research on the mechanism of viral infection, antiviral therapy and vaccine development more efficiently.

Reference

• Nikonov, O. S., et al., Enteroviruses: classification, diseases they cause, and approaches to development of antiviral drugs. Biochemistry (moscow) 82 (2017): 1615-1631.

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