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Review
. 2017 Aug 3;8:1469.
doi: 10.3389/fmicb.2017.01469. eCollection 2017.

Advances in Developing Therapies to Combat Zika Virus: Current Knowledge and Future Perspectives

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Free PMC article
Review

Advances in Developing Therapies to Combat Zika Virus: Current Knowledge and Future Perspectives

Ashok Munjal et al. Front Microbiol. .
Free PMC article

Abstract

Zika virus (ZIKV) remained largely quiescent for nearly six decades after its first appearance in 1947. ZIKV reappeared after 2007, resulting in a declaration of an international "public health emergency" in 2016 by the World Health Organization (WHO). Until this time, ZIKV was considered to induce only mild illness, but it has now been established as the cause of severe clinical manifestations, including fetal anomalies, neurological problems, and autoimmune disorders. Infection during pregnancy can cause congenital brain abnormalities, including microcephaly and neurological degeneration, and in other cases, Guillain-Barré syndrome, making infections with ZIKV a substantial public health concern. Genomic and molecular investigations are underway to investigate ZIKV pathology and its recent enhanced pathogenicity, as well as to design safe and potent vaccines, drugs, and therapeutics. This review describes progress in the design and development of various anti-ZIKV therapeutics, including drugs targeting virus entry into cells and the helicase protein, nucleosides, inhibitors of NS3 protein, small molecules, methyltransferase inhibitors, interferons, repurposed drugs, drugs designed with the aid of computers, neutralizing antibodies, convalescent serum, antibodies that limit antibody-dependent enhancement, and herbal medicines. Additionally, covalent inhibitors of viral protein expression and anti-Toll-like receptor molecules are discussed. To counter ZIKV-associated disease, we need to make rapid progress in developing novel therapies that work effectually to inhibit ZIKV.

Keywords: Guillain-Barré Syndrome; Zika virus; drugs; microcephaly; therapies.

Figures

FIGURE 1
FIGURE 1
Mode of entry of Zika virus (ZIKV) and various drugs inhibiting viral entry and replication (1) ZIKV binds to cell receptors including AXL, DC-SIGN, Tyro3, TIM, and TAM. (2) Clathrin-dependent endocytosis. (3) Endosome mediated transport of ZIKV. (4) Fusion of virus membrane with host endosomal membrane, which depends on the pH. (5) Uncoating (6) The positive-sense genomic ssRNA is translated into a polyprotein, which is cleaved into all structural and non-structural proteins. Replication occurs at the surface of endoplasmic reticulum in cytoplasmic viral factories. A dsRNA genome is synthesized from the genomic ssRNA(+) (7) Virus assembly takes place at the endoplasmic reticulum. (8) At the endoplasmic reticulum, virions bud and are transported to the golgi apparatus. (9) In the golgi, prM protein is cleaved and maturation of the virion takes places. (10) Virions are released by exocytosis. (11) Obatoclax and chloroquineinhibit the acidic environment of endolysosomal vesicles. Squalamine, a cationic chemical, disturbs the electrostatic interaction between virus and host membranes during fusion and budding. (12) Cavinafungin, an alaninal-containing lipopeptide of fungal origin, inhibits ZIKV polyprotein processing and also the cleavage of signal peptide of host proteins. (13) Nanchangmycin, a polyether obtained from Streptomyces nanchangensis; small drug-like molecules, ZINC33683341 and ZINC49605556 block the receptor thus inhibiting the ZIKV entry. (14) TIM1 mediated entry is inhibited by Duramycin-biotin.
FIGURE 2
FIGURE 2
Various drugs involved in inhibition of virus replication at different stages. (1) Flaviviral NS5 has two major catalytic domains: RNA-dependent RNA polymerase (RdRp) and methyltransferase domain. Nucleoside analogs like 2′-C-methylated nucleosides, 7-deaza-2′-C-methyladenosine, Sofosbuvir may incorporate during the polymerase activity of RdRp in the viral nascent RNA chain and cause premature termination of RNA synthesis. The 2′-fluoro-2-C-methyl-UTP binds to the active site on NS5. (2) Methyltransferase domain is responsible for transferring mRNA cap. Sinefungin, an adenosine derivative, isolated from Streptomyces griseoleus, inhibit S-adenosyl-1-methionine (SAM), the natural substrate for methyltransferases and inhibit the methyltransferase activity. (3) Helicase crystal structure reveals a conserved triphosphate pocket and a positively charged tunnel for the accommodation of RNA. The helicase-activation is inhibited in the presence of divalent cation, due to extended conformation adopted by GTPγS in such conditions. (4) Tetrapeptide-Boronic acid is a potent inhibitor of NS2B-NS3 protease. Berberine, Myricetin, Epigallocatechingallate binds with affinity to NS3 protease and also inhibit the ZIKV replication. (5) Small-molecule inhibitor ST-148 inhibits capsid. (6) Ribavirin inhibits host inosine monophosphate dehydrogenase and viral polymerase. (7) Repurposed drugs like Chloroquine, azithromycin, niclosomide are used to treat ZIKV infection.
FIGURE 3
FIGURE 3
Antibody-dependent enhancement (ADE) of Zika virus (ZIKV) and strategies to limit it. (A) General ADE mechanism. (1) FcγRs are receptors present on the surface of various immune cells. Binding of antibody along with ZIKV results in (2) internalization of immune complexes into cells, (3) a reduction of IL12, TNFα, and IFNγ expression levels, and (4) increased levels of IL6 and IL12 (5). IL10 acts in an autocrine manner and binds to its own receptor (6), inhibiting the JAK-STAT pathway (7), which leads to reduced IRF1 production (8) and reduced IFN-stimulated response element (IRF1) production, resulting in decreased nitric oxide production. Nitric oxide, a diffusible radical antimicrobial and anti-viral, is reduced (9), which results in an increase in the number of infectious virus particles (10) IFNα/β are inhibited (11), diffuse out from the cell (12), and bind to their own receptors to reduce JAK-STAT signaling. (B) Antibodies engineered to prevent ADE (12) Engineered antibodies having LALA mutations in their Fc region are able to neutralize virus but fail to bind to FcγRs, thus preventing ADE.

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