Research Models and Tools for the Identification of Antivirals and Therapeutics against Zika Virus Infection

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Abstract

Zika virus recently re-emerged and caused global outbreaks mainly in Central Africa, Southeast Asia, the Pacific Islands and in Central and South America. Even though there is a declining trend, the virus continues to spread throughout different geographical regions of the world. Since its re-emergence in 2015, massive advances have been made regarding our understanding of clinical manifestations, epidemiology, genetic diversity, genomic structure and potential therapeutic intervention strategies. Nevertheless, treatment remains a challenge as there is no licensed effective therapy available. This review focuses on the recent advances regarding research models, as well as available experimental tools that can be used for the identification and characterization of potential antiviral targets and therapeutic intervention strategies.

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Most cited references 148

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Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Miao Xu, Emily M Lee, Zhexing Wen … (2016)

In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

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Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys.

P Abbink, R. A. Larocca, R. A. De La Barrera … (2016)

Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans.

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Perspective: Evolution and detection of genetic robustness.

J Arjan G M de Visser, Joachim Hermisson, Günter P. Wagner … (2003)

Robustness is the invariance of phenotypes in the face of perturbation. The robustness of phenotypes appears at various levels of biological organization, including gene expression, protein folding, metabolic flux, physiological homeostasis, development, and even organismal fitness. The mechanisms underlying robustness are diverse, ranging from thermodynamic stability at the RNA and protein level to behavior at the organismal level. Phenotypes can be robust either against heritable perturbations (e.g., mutations) or nonheritable perturbations (e.g., the weather). Here we primarily focus on the first kind of robustness--genetic robustness--and survey three growing avenues of research: (1) measuring genetic robustness in nature and in the laboratory; (2) understanding the evolution of genetic robustness: and (3) exploring the implications of genetic robustness for future evolution.

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Author and article information

Journal

Journal ID (nlm-ta): Viruses

Journal ID (iso-abbrev): Viruses

Journal ID (publisher-id): viruses

Title: Viruses

Publisher: MDPI

ISSN (Electronic): 1999-4915

Publication date (Electronic): 30 October 2018

Publication date Collection: November 2018

Volume: 10

Issue: 11

Electronic Location Identifier: 593

Affiliations

[1 ]Institute of Virology and Immunology, 3012 Bern, Switzerland; nathalie.vielle@ 123456vetsuisse.unibe.ch

[2 ]Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland

[3 ]Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland

Author notes

[* ]Correspondence: marco.alves@ 123456vetsuisse.unibe.ch (M.P.A.); volker.thiel@ 123456vetsuisse.unibe.ch (V.T.); stephanie.pfaender@ 123456vetsuisse.unibe.ch (S.P.); Tel.: +41-31-631-24-83 (M.P.A.); +41-31-631-24-13 (V.T.); +41-31-631-25-02 (S.P.)

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Volker Thiel https://orcid.org/0000-0002-5783-0887

Article

Publisher ID: viruses-10-00593

DOI: 10.3390/v10110593

PMC ID: 6265910

PubMed ID: 30380760

SO-VID: d522a255-aaf7-4454-bb08-c9f9678791e6

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Research Models and Tools for the Identification of Antivirals and Therapeutics against Zika Virus Infection

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Zika Virus

Most cited references 148

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys.

Perspective: Evolution and detection of genetic robustness.

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