Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid spread, and an association with severe neurological and ophthalmological complications. Currently, no specific antiviral therapy against ZIKV is available, and treatments are palliative and mainly directed to symptoms relief, such as fever and rash, by administering antipyretics, anti-histamines, and fluids for dehydration. Nevertheless, lately, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from repurposing of specific compounds with known antiviral activity to the screening of libraries and of natural compounds. The identified antiviral candidates include drugs targeting viral components (structural proteins and enzymes), as well as cellular ones. Here, we present an updated review of current knowledge about anti-ZIKV strategies, focusing on host-directed antivirals as a realistic alternative to combat ZIKV infection.

Genome-wide CRISPR screen for Zika virus resistance in human neural cells

“…Our finding that the endosome-lysosome pathway is utilized by ZIKV is consistent with recent reports that the blockade of endocytosis using chloroquine reduced ZIKV infection (10,(31)(32)(33). Other recently identified protective smallmolecule compounds against ZIKV infection have also been shown to interfere with this pathway (34,35). We reason that many of these genes were not identified in screens using cancer cell lines because they are considered essential for cancer cells and their ablations disrupt cellular fitness (20,21).…”

The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides.

“…Despite current potential protection from herd and self-immunity, environmental factors, and host-vector-virus interactions that keep ZIKV in the low incidence figures [1], [52], [53], [54], [55], preventing ZIKV and other arbovirus infections should be a priority. In recent years, many compounds have been proposed as potential anti-ZIKV agents following in vitro results [24], [25], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65]. Some of these drugs have an extensive background in the medical field and offer attractive options, either alone or in combination, for treatment and perhaps prophylaxis of ZIKV infections; however, most of them remain inadequate to be used during pregnancy.…”

“…Nucleotide biosynthesis inhibitors such as ribavirin, brequinar, and mycophenolic acid (MPA) have been shown extensively to inhibit a wide array of viral infections both in vitro and in vivo [17], [18], [19], [20], [21] [22], [23]. In addition, a number of small compounds that possess antiviral function through the depletion of intracellular nucleotide pools have been identified, suggesting that this cellular pathway may be a prime target for antiviral development [24], [25], [26], [27], [28]. Unfortunately, many of these compounds have numerous side effects and are not approved for use in high risk populations such as pregnant women or children, thus the development of safe and pregnancy-acceptable nucleotide biosynthesis inhibitors would be ideal candidates as antivirals.…”

Baculovirus Surface Display of Zika Virus Envelope Protein Protects against Virus Challenge in Mouse Model

“…The structural proteins play a significant role in viral entry, fusion and assembly. E protein is the primary target of neutralizing antibodies (Abbink et al 2017;Dai et al 2018;Saiz et al 2018). Two genetic strains of ZIKV are identified, African and Asian/American, with only one serotype (Richner et al 2017).…”

“…Although ZIKV vaccine development has had a quick head start, further development may be hampered because of the decline in cases globally (Durbin and Wilder-Smith 2017). Currently, there are no authorized ZIKV vaccines and specific antivirals approved for clinical use, making prophylactic and effective vaccination the first and best approach to combat the disease (da Silva et al 2018;Saiz et al 2018). Furthermore, new outbreaks of ZIKV are unpredictable.…”