A Review of the Ongoing Research on Zika Virus Treatment

Silva, Suely da; Martins, Décio Rodrigues; Jardim, Ana Carolina Gomes

doi:10.3390/v10050255

Cited by 38 publications

(35 citation statements)

References 99 publications

(104 reference statements)

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“…Despite current potential protection due to herd and selfimmunity, environmental factors, and host-vector-virus interactions that keep ZIKV at low incidence (1,55,56), preventing ZIKV and other arbovirus infections should be a priority. In recent years, many compounds have been proposed as potential anti-ZIKV agents following in vitro results (29,30,(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). Some of these drugs have an extensive background in the medical field and offer attractive options, either alone or in combination, for treatment and perhaps prophylaxis of ZIKV infections; however, most of them remain inadequate to be used during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

Kottkamp

Jesus

Grande

et al. 2019

J Virol

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Arthropod-borne viruses represent a significant public health threat worldwide, yet there are few antiviral therapies or prophylaxes targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy-acceptable antiviral compounds is to repurpose well-known and widely used FDA-approved drugs. In this study, we addressed the antiviral role of atovaquone, an FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides, indicating that atovaquone functions through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner, providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women and children.IMPORTANCE The ability to protect vulnerable populations such as pregnant women and children from Zika virus and other arbovirus infections is essential to preventing the devastating complications induced by these viruses. One class of antiviral therapies may lie in known pregnancy-acceptable drugs that have the potential to mitigate arbovirus infections and disease, yet this has not been explored in detail. In this study, we show that the common antiparasitic drug atovaquone inhibits arbovirus replication through intracellular nucleotide depletion and can impair ZIKV infection in an ex vivo human placental explant model. Our study provides a novel function for atovaquone and highlights that the rediscovery of pregnancy-acceptable drugs with potential antiviral effects can be the key to better addressing the immediate need for treating viral infections and preventing potential birth complications and future disease.

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Section: Discussionmentioning

confidence: 99%

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

Kottkamp

Jesus

Grande

et al. 2019

J Virol

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show abstract

“…Despite current potential protection from herd and self-immunity, environmental factors, and host-vector-virus interactions that keep ZIKV in the low incidence figures [1], [52], [53], [54], [55], preventing ZIKV and other arbovirus infections should be a priority. In recent years, many compounds have been proposed as potential anti-ZIKV agents following in vitro results [24], [25], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65]. Some of these drugs have an extensive background in the medical field and offer attractive options, either alone or in combination, for treatment and perhaps prophylaxis of ZIKV infections; however, most of them remain inadequate to be used during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…Nucleotide biosynthesis inhibitors such as ribavirin, brequinar, and mycophenolic acid (MPA) have been shown extensively to inhibit a wide array of viral infections both in vitro and in vivo [17], [18], [19], [20], [21] [22], [23]. In addition, a number of small compounds that possess antiviral function through the depletion of intracellular nucleotide pools have been identified, suggesting that this cellular pathway may be a prime target for antiviral development [24], [25], [26], [27], [28]. Unfortunately, many of these compounds have numerous side effects and are not approved for use in high risk populations such as pregnant women or children, thus the development of safe and pregnancy-acceptable nucleotide biosynthesis inhibitors would be ideal candidates as antivirals.…”

Section: Introductionmentioning

confidence: 99%

The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides.

Kottkamp

Jesus

Grande

et al. 2018

Preprint

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Arthropod-borne viruses represent a significant public health threat worldwide yet there are few antiviral therapies or prophylaxis targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy friendly antiviral compounds is to repurpose well-known and widely used FDA approved drugs. In this study, we addressed the antiviral role of atovaquone, a FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides indicating that atovaquone is functioning through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women.

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“…Several therapeutic approaches that target the different steps of the viral replication cycle ( Figure 1 ) have been developed (reviewed in [ 30 , 31 , 32 ]). In general, drug candidates can be classified according to their mode of action, either directed against viral targets (direct-acting antivirals) or acting against cellular targets (host-targeting antivirals).…”

Section: Replication Cycle and Potential Intervention Strategiesmentioning

confidence: 99%

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

Alves

Vielle

Thiel

et al. 2018

Viruses

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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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A Review of the Ongoing Research on Zika Virus Treatment

Cited by 38 publications

References 99 publications

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides.

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

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