Emerging Therapeutics in the Fight Against EV-D68: A Review of Current Strategies

Abstract

Enterovirus-D68 (EV-D68) was first identified in 1962 in pediatric patients with acute respiratory conditions in California, USA (US). From the 1970s to 2005, EV-D68 was underestimated due to limited data and serotyping methods. In 2014, the United States experienced outbreaks of acute flaccid myelitis (AFM) in children EV-D68 positive. WIN-like compounds (pleconaril, pocapavir, and vapendavir) bind to the virus capsid and have been tested against various enteroviruses (EVs) in clinical trials. However, these compounds encountered issues with resistance and adverse effects, which impeded their approval by the Food and Drug Administration (FDA). Presently, the medical field lacks FDA-approved antiviral treatments or vaccines for EV-D68. Ongoing research efforts are dedicated to identifying viable therapeutics to address EV-D68 infections. This review explores the current advancements in antiviral therapies and potential therapeutics to mitigate the significant impact of EV-D68 infection control.

Keywords: WIN‐like compounds; acute flaccid myelitis; broad‐spectrum antiviral; contemporary strains; drug‐resistance; enterovirus‐D68; type‐I interferon; viral life cycle.

FIGURE 1

Sialic acid/ICAM‐5 aids the entry of the EVD68 into the host cell. Upon attachment with the receptor, it causes the restructuring of the capsid. It stimulates the formation of intermediate “A particle” that causes perforations in the endosome and aids viral RNA genome delivery. The translation process immediately starts upon entry into the cytosol, and polypeptide processing initiates. The proteolysis of polypeptide separates structural (VP1, VP2, VP3, and VP4) and non‐structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). Further, the self‐cleavage activity of VP0 leads to the formation of VP2 and VP4 proteins, which further involves capsid maturation. The 3Dpol further proceeds the replication process. The synthesis of (−)ssRNA becomes the source of generating multiple copies of the viral RNA genome. The Vpg‐linked (−)ssRNA and structural proteins help form new matured viral particles. The mature viral particles are released from cytosol either in a non‐lytic or lytic manner.

FIGURE 2

(a) During the replication process, VP0, VP1, and VP3 form a trimeric unit called a protomer. Five units of protomer form pentameric unit, and 12 units of these further form icosahedral capsid. (b) Proteolysis causes cleavage of VP0 protein and forms VP2 and VP4 proteins, which further helps in the assembly of viral particles and capsid maturation.