Therapeutic Advances Against ZIKV: A Quick Response, a Long Way to Go

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that spread throughout the American continent in 2015 causing considerable worldwide social and health alarm due to its association with ocular lesions and microcephaly in newborns, and Guillain–Barré syndrome (GBS) cases in adults. Nowadays, no licensed vaccines or antivirals are available against ZIKV, and thus, in this very short time, the scientific community has conducted enormous efforts to develop vaccines and antivirals. So that, different platforms (purified inactivated and live attenuated viruses, DNA and RNA nucleic acid based candidates, virus-like particles, subunit elements, and recombinant viruses) have been evaluated as vaccine candidates. Overall, these vaccines have shown the induction of vigorous humoral and cellular responses, the decrease of viremia and viral RNA levels in natural target organs, the prevention of vertical and sexual transmission, as well as that of ZIKV-associated malformations, and the protection of experimental animal models. Some of these vaccine candidates have already been assayed in clinical trials. Likewise, the search for antivirals have also been the focus of recent investigations, with dozens of compounds tested in cell culture and a few in animal models. Both direct acting antivirals (DAAs), directed to viral structural proteins and enzymes, and host acting antivirals (HAAs), directed to cellular factors affecting all steps of the viral life cycle (binding, entry, fusion, transcription, translation, replication, maturation, and egress), have been evaluated. It is expected that this huge collaborative effort will produce affordable and effective therapeutic and prophylactic tools to combat ZIKV and other related still unknown or nowadays neglected flaviviruses. Here, a comprehensive overview of the advances made in the development of therapeutic measures against ZIKV and the questions that still have to be faced are summarized.

Old Drugs with New Tricks: Efficacy of Fluoroquinolones to Suppress Replication of Flaviviruses

“…Moreover many flaviviruses, such as Zika (ZIKV), dengue (DENV), tick-borne encephalitis (TBEV), West Nile (WNV), and Japanese encephalitis (JEV) virus [7][8][9] are categorized as emerging pathogens due to rising incidence and expanding geographic range [10,11]. Effective antiviral drugs could abate flavivirus transmission and disease burden, but to date no drugs for treatment of flavivirus infections have been brought to market because efforts to develop anti-flaviviral drugs have been unsuccessful [12,13]. Most anti-flaviviral drug candidates have stalled at the point of hit-to-lead optimization due to poor drug-like properties [14][15][16].…”

Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections

“…Zika virus (ZIKV) spread throughout the American continent in 2015 causing considerable worldwide social and medical alarm due to its association with congenital disorders [ 29 ], such as microcephaly in newborns, or severe neurological manifestations in adults [ 40 ]. This led the World Health Organization (WHO) to declare a Public Health Emergency of International Concern (PHEIC) in February 2016 [ 41 ]. JEV is a notable cause of encephalitis in Asia [ 36 ].…”

“…Treatment with DAAs often fails due to the rapid generation of drug-resistant viruses [ 58 ], as exemplified by resistance-associated substitutions (RASs, amino acid substitutions in the viral proteins) in the case of HCV infections [ 59 , 60 ], thus emphasizing the clinical challenge these resistance mutations represent for the management of patients with HCV and other viral infections [ 61 ]. Since almost all members of the Flaviviridae family share common host factors, HDA-based therapies are a feasible solution to overcome these drawbacks [ 41 ]. Moreover, targeting host proteins required by different viral species can provide a broad-spectrum therapy.…”

“…The most cost and time effective strategy for the development of broad-spectrum antivirals is drug repurposing. Consequently, pharmacological compounds that target host functions key to the viral life cycle are being tested for activity against multiple viruses [ 41 , 64 , 65 , 66 , 67 , 68 ]. Chemicals targeting the cellular kinome have been explored as novel potential targets for antiviral drug development.…”

Clinical evidences on the antiviral properties of macrolide antibiotics in the COVID-19 era and beyond

“…Currently there is no vaccine or antiviral treatment against Zika virus infections. 74,75 A number of different therapeutics were tested for their potential effect against the virus. One of the tested drugs is AZI, which showed inhibitory effects in vitro and in some animal models.…”