Recognizing the Global Impact of Zika Virus Infection during Pregnancy

Honein, Margaret A.

doi:10.1056/nejme1801398

Cited by 24 publications

(16 citation statements)

References 11 publications

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“…It remains unknown when the next outbreak of ZIKV will occur, yet we know through past devastating epidemics, in which millions of individuals, including women and children, were affected by this virus that we still have an urgent need for effective therapies against ZIKV infection (16,53,54). 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.…”

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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“…For symmetrically small neonates with SGA, head circumference may meet criteria for microcephaly owing to growth restriction and not disrupted brain development, particularly if no abnormalities are detected on neuroimaging. 31 Silva et al 32 found fetal growth restriction was strongly associated with microcephaly. Understanding the association of antenatal Zika virus infection and fetal growth can inform the evaluation of neonates with congenital Zika virus exposure and microcephaly.…”

Section: Discussionmentioning

confidence: 99%

Maternal Zika Virus Infection

Iwamoto

Lash

et al. 2019

Obstetrics &Amp; Gynecology

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“…It remains unknown when the next outbreak of ZIKV will occur, yet we know through past devastating epidemics, in which thousands of women and children were affected by this virus that we still have an urgent need for effective therapies against ZIKV infection [11], [50], [51]. 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.…”

Section: Discussionmentioning

confidence: 99%

“…Pregnant women carry a particularly high risk for ZIKV and other arbovirus-related complications [10], [11], [12]. Importantly, the capacity of the virus to infect trophoblasts, Hofbauer macrophages and endothelial cells [1], [13], thus allowing it to infect the fetus at any stage of growth, challenges the protective function of the placenta in the materno-fetal interface [14],[15].…”

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.

show abstract

Recognizing the Global Impact of Zika Virus Infection during Pregnancy

Cited by 24 publications

References 11 publications

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

Maternal Zika Virus Infection

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

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