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Molecules
Volume 25
Issue 20
10.3390/molecules25204813
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Article

Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

by
Marcella Bassetto
1,
Cecilia M. Cima
2,
Mattia Basso
2,
Martina Salerno
2,
Frank Schwarze
3,
Daniela Friese
3,
Joachim J. Bugert
3 and
Andrea Brancale
2,*
1
Department of Chemistry, Swansea University, Swansea SA2 8PP, UK
2
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK
3
Institut für Mikrobiologie der Bundeswehr, 80937 Munich, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Katherine Seley-Radtke
Molecules 2020, 25(20), 4813; https://doi.org/10.3390/molecules25204813
Received: 26 September 2020 / Revised: 14 October 2020 / Accepted: 16 October 2020 / Published: 20 October 2020
(This article belongs to the Special Issue Advances in Nucleoside/Nucleotides and Nucleic Acid Chemistry: A Theme Issue in Honor of Prof. Dr. Piet Herdewijn)
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Abstract

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism. View Full-Text
Keywords: antiviral agents; aryloxyphosphoramidate prodrugs; Zika virus; in vitro screening antiviral agents; aryloxyphosphoramidate prodrugs; Zika virus; in vitro screening
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MDPI and ACS Style

Bassetto, M.; Cima, C.M.; Basso, M.; Salerno, M.; Schwarze, F.; Friese, D.; Bugert, J.J.; Brancale, A. Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections. Molecules 2020, 25, 4813. https://doi.org/10.3390/molecules25204813

AMA Style

Bassetto M, Cima CM, Basso M, Salerno M, Schwarze F, Friese D, Bugert JJ, Brancale A. Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections. Molecules. 2020; 25(20):4813. https://doi.org/10.3390/molecules25204813

Chicago/Turabian Style

Bassetto, Marcella, Cecilia M. Cima, Mattia Basso, Martina Salerno, Frank Schwarze, Daniela Friese, Joachim J. Bugert, and Andrea Brancale. 2020. "Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections" Molecules 25, no. 20: 4813. https://doi.org/10.3390/molecules25204813

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