Probenecid Inhibits Influenza A(H5N1) and A(H7N9) Viruses In Vitro and in Mice

Murray, Jackelyn; Martin, David E.; Hosking, Sarah; Orr-Burks, Nichole; Hogan, Robert J.; Tripp, Ralph A.

doi:10.3390/v16010152

Cited by 3 publications

(1 citation statement)

References 77 publications

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“… 7 Subtype H7N9 influenza virus can bind to both α2,3 sialic acid receptors and α2,6 sialic acid receptors, which are distributed in the upper‐respiratory and digestive tracts of both poultry and humans. 8 , 9 Influenza type‐B viruses also bind to α2,6 sialic acid receptors, similar to H1N1 and H3N2 subtypes. 10 , 11 In the influenza mouse model, BALB/c mice show increased expression of α2,3‐linked sialic acid receptors in the lungs.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a humanized ST6GAL1 mouse model for influenza research

Chao,

Feng,

Qian

et al. 2024

Anim Models and Exp Med

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BackgroundThis study aimed to construct and characterize a humanized influenza mouse model expressing hST6GAL1.MethodsHumanized fragments, consisting of the endothelial cell‐specific K18 promoter, human ST6GAL1‐encoding gene, and luciferase gene, were microinjected into the fertilized eggs of mice. The manipulated embryos were transferred into the oviducts of pseudopregnant female mice. The offspring were identified using PCR. Mice exhibiting elevated expression of the hST6GAL1 gene were selectively bred for propagation, and in vivo analysis was performed for screening. Expression of the humanized gene was tested by performing immunohistochemical (IHC) analysis. Hematologic and biochemical analyses using the whole blood and serum of humanized hST6GAL1 mice were performed.ResultsSuccessful integration of the human ST6GAL1 gene into the mouse genome led to the overexpression of human SiaT ST6GAL1. Seven mice were identified as carrying copies of the humanized gene, and the in vivo analysis indicated that hST6GAL1 gene expression in positive mice mirrored influenza virus infection characteristics. The IHC results revealed that hST6GAL1 was expressed in the lungs of humanized mice. Moreover, the hematologic and biochemical parameters of the positive mice were within the normal range.ConclusionA humanized influenza mouse model expressing the hST6GAL1 gene was successfully established and characterized.

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Section: Introductionmentioning

confidence: 99%

Establishment of a humanized ST6GAL1 mouse model for influenza research

Chao,

Feng,

Qian

et al. 2024

Anim Models and Exp Med

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Probenecid Inhibits Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase Mitogen-Activated Protein Kinase Pathways in Regulating Respiratory Syncytial Virus Response

Jones,

Bergeron,

Martin

et al. 2024

IJMS

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We examined the effect of probenecid in regulating the ERK and JNK downstream MAPK pathways affecting respiratory syncytial virus replication. Background: We have previously shown that probenecid inhibits RSV, influenza virus, and SARS-CoV-2 replication in vitro in preclinical animal models and in humans. In a Phase two randomized, placebo-controlled, single-blind, dose range-finding study using probenecid to treat non-hospitalized patients with symptomatic, mild-to-moderate COVID-19, we previously showed that a 1000 mg twice daily treatment for 5 days reduced the median time to viral clearance from 11 to 7 days, and a 500 mg twice daily treatment for 5 days reduced the time to viral clearance from 11 to 9 days more than the placebo. Methods: In this study, we sought to determine the mechanism of action of the probenecid inhibition of RSV replication in human respiratory epithelial (A549) cells. Results: We show that probenecid inhibits the RSV-induced phosphorylation of JNKs and ERKs and the downstream phosphorylation of c-jun, a component of the AP-1 transcription complex needed for virus replication. The inhibition of JNKs by probenecid reversed the repression of transcription factor HNF-4. Conclusion: The probenecid inhibition of JNK and ERK phosphorylation involves the MAPK pathway that precludes virus replication.

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Probenecid Inhibits Human Metapneumovirus (HMPV) Replication In Vitro and in BALB/c Mice

Bergeron,

Crabtree,

Nagy

et al. 2024

Viruses

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Human metapneumovirus (HMPV) is an important cause of acute respiratory tract infection and causes significant morbidity and mortality. There is no specific antiviral drug to treat HMPV or vaccine to prevent HMPV. This study determined if probenecid, a host-targeting antiviral drug, had prophylactic (pre-virus) or therapeutic (post-virus) efficacy to inhibit HMPV replication in LLC-MK2 cells in vitro and in the lungs of BALB/c mice. This study showed that ≥0.5 μM probenecid significantly inhibited HMPV replication in vitro, and 2–200 mg/kg probenecid prophylaxis or treatment reduced HMPV replication in BALB/c mice.

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Probenecid Inhibits Influenza A(H5N1) and A(H7N9) Viruses In Vitro and in Mice

Cited by 3 publications

References 77 publications

Establishment of a humanized ST6GAL1 mouse model for influenza research

Establishment of a humanized ST6GAL1 mouse model for influenza research

Probenecid Inhibits Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase Mitogen-Activated Protein Kinase Pathways in Regulating Respiratory Syncytial Virus Response

Probenecid Inhibits Human Metapneumovirus (HMPV) Replication In Vitro and in BALB/c Mice

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