Dengue, West Nile, and Zika Viruses: Potential Novel Antiviral Biologics Drugs Currently at Discovery and Preclinical Development Stages

Abstract

Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital malformations (e.g., microcephaly) and, in some situations, death. Moreover, outbreaks also have major socioeconomic repercussions, especially in already vulnerable societies. Thus far, only generic symptoms relief is possible, as there are no specific treatments available yet. Dengvaxia was the world's first dengue vaccine. However, it is not fully effective. Prophylactic approaches against West Nile and Zika viruses are even more limited. Therefore, therapeutic strategies are required and will be discussed hereafter. We will first briefly present these viruses' epidemiology, life cycle and structure. Then, we introduce the clinical presentation, diagnosis approaches and available vaccines. Finally, we list and discuss promising compounds at discovery and preclinical development stages already deposited at the GlobalData database and divided into three main types, according to therapeutic molecule: antibody-based, peptide-based molecules and, other compounds. To conclude, we discuss and compare promising developments, useful for future therapies against these three flaviviruses of major concern to human health.

Keywords: West Nile virus; Zika virus; dengue virus; flavivirus; therapeutics.

Figure 1

Aedes aegypti distribution worldwide. The map indicates the total number of annual life-cycle completions (LCC) of A. aegypti, with occurrence data overlaid. A. aegypti is a recognized competent vector for both DENV and ZIKV. Adapted with permission from Ref. [12]. Copyright 2020 Iwamura, T.; Guzman-Holst, A.; Murray, K.A.

Figure 2

Estimated potential global distribution of Culex quinquefasciatus. The colors represent the suitability level from 0 (blue) to 1 (red). C. quinquefasciatus is a known competent biological vector of WNV. In addition, recent evidence suggested its potential as vector for ZIKV [13,14]. Adapted with permission from Ref. [13]. Copyright 2018 Alaniz, A.J.; Carvajal, M.A.; Bacigalupo, A.; Cattan, P.E.

Figure 3

Viral life cycle. After entering host cells by clathrin-mediated endocytosis (1), membrane fusion of the viral envelope and the cell membrane occurs (2). Viral genome is released into the cytoplasm (3) and translated into a single polyprotein, later cleaved into the three structural and seven non-structural proteins (4). Next, replication occurs surrounding the endoplasmic reticulum (ER) and lipid droplets (LDs) (5), followed by viral packaging and assembly to form infectious viral particles (6), which are then released through exocytosis (7). The three flaviviruses discussed here share similar virion structure and mode of infection, besides being also all mosquito-borne. Adapted with permission from Ref. [4]. Copyright 2020 Silva, N.M.; Santos, N.C.; Martins, I.C.