Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview

Abstract

Flaviviruses cause numerous pathologies in humans across a broad clinical spectrum with potentially severe clinical manifestations, including hemorrhagic and neurological disorders. Among human flaviviruses, some viral proteins show high conservation and are good candidates as targets for drug design. From an epidemiological point of view, flaviviruses cause more than 400 million cases of infection worldwide each year. In particular, the Yellow Fever, dengue, West Nile, and Zika viruses have high morbidity and mortality-about an estimated 20,000 deaths per year. As they depend on human vectors, they have expanded their geographical range in recent years due to altered climatic and social conditions. Despite these epidemiological and clinical premises, there are limited antiviral treatments for these infections. In this review, we describe the major compounds that are currently under evaluation for the treatment of flavivirus infections and the challenges faced during clinical trials, outlining their mechanisms of action in order to present an overview of ongoing studies. According to our review, the absence of approved antivirals for flaviviruses led to in vitro and in vivo experiments aimed at identifying compounds that can interfere with one or more viral cycle steps. Still, the currently unavailability of approved antivirals poses a significant public health issue.

Keywords: DENV; TBEV; WNV; YFV; ZIKV; antiviral; drug; flavivirus; public health; zoonotic.

Figure 1

Flaviviral genome. Flaviviral genome contains genes for structural and non-structural proteins, which are flanked by two non-coding regions (NCR) at 5′ and 3′. Encoded Polyproteins are cleaved by cellular and viral proteases, releasing three structural proteins and seven non-structural ones. Protein M is initially released as a precursor (prM) and subsequently cleaved and released as a mature protein M. Modified by King and colleagues [14].

Figure 2

Flavivirus life cycle. The viruses bind to receptors on the host cell and enter via receptor-mediated endocytosis. The viral envelope merges with the host membrane in endosomes, and the viral capsid disassembles, allowing the viral genome to enter the cytoplasm. The positive-sense RNA is translated in the ER into a single polyprotein, which is co- and post-translationally digested by viral and host proteases. In specialized ER-derived membrane compartments, the viral-RNA-dependent RNA polymerase replicates the viral genome. The assembled viral nucleocapsids sprout into the ER lumen and exit the cell via the secretory route. Non-infectious, immature viral and subviral particles are produced and transmitted by the trans-Golgi network. The host protease furin cleaves the immature virion particles, resulting in mature, infectious particles, which are subsequently released by exocytosis [78,79].

Figure 3

Signaling mechanisms of viral entry receptors. Flavivirus entry receptors affect a variety of pathways, including cytoskeleton alterations via integrins, endocytosis, proliferation, and cell survival via PI3K-AKT (TIM and TAM receptors), and immune response downregulation by JAK-STAT.