Zika Virus: Origins, Pathological Action, and Treatment Strategies

Abstract

The Zika virus (ZIKV) global epidemic prompted the World Health Organization to declare it a 2016 Public Health Emergency of International Concern. The overwhelming experience over the past several years teaches us that ZIKV and the associated neurological complications represent a long-term world-wide challenge to public health. Although the number of ZIKV cases in the Western Hemisphere has dropped since 2016, the need for basic research and anti-ZIKV drug development remains strong. Re-emerging viruses like ZIKV are an ever-present threat in the 21st century where fast transcontinental travel lends itself to viral epidemics. Here, we first present the origin story for ZIKV and review the rapid progress researchers have made toward understanding of the ZIKV pathology and in the design, re-purposing, and testing-particularly in vivo-drug candidates for ZIKV prophylaxis and therapy ZIKV. Quite remarkably, a short, but intensive, drug-repurposing effort has already resulted in several readily available FDA-approved drugs that are capable of effectively combating the virus in infected adult mouse models and, most importantly, in both preventing maternal-fetal transmission and severe microcephaly in newborns in pregnant mouse models.

Keywords: ZIKV; drugs; in vivo; maternal transmission; re-purposing.

Figure 1

ZIKV infects multiple tissues in humans. Illustration depicting the tissue and cell types that are targeted by ZIKV. Skin is represented by a cartoon of a fibroblast cell. OBGYN tissues are represented by a cartoon of the villus of the placenta and its different cell layers, embryonic brain tissues depicted by a cartoon of the embryonic brain with neural progenitor cells, testis are depicted by a cartoon drawing of spermatozoa.

Figure 2

Anti-ZIKV drugs targeting the different steps in the viral life cycle. Emricasan targets caspase-3 activity to prevent cell death. Z2 peptide targets ZIKV cell entry. 25-hydroxycholesterol and chloroquine interfere with lipid homeostasis and autophagy to disrupt viral particle release after endocytosis. Temoporfin, nitazoxanide, niclosamide, and viperin block NS2B/NS3 protease activity to prevent viral replication. Sofosbuvir, merimepodib, N-(4-hydrophenyl) retinamide, 7-deaza-2′-C-methyladenosine, NITD008, BCX4430, and ribavarin block ZIKV NS5 polymerase activity to prevent viral replication. Ribavarin and merimepodib block IMPDH, an enzyme involved in de novo synthesis of guanine nucleotides. Niclosamide, EGCG, and cavinafungin block CDKs and prevent viral replication.