The Oxindole GW-5074 Inhibits JC Polyomavirus Infection and Spread by Antagonizing the MAPK-ERK Signaling Pathway

Kaiserman, Jacob; O’Hara, Bethany A.; Garabian, Kaitlin; Lukacher, Avraham; Haley, Sheila A.; Atwood, Walter J.

doi:10.1128/mbio.03583-22

Cited by 2 publications

(4 citation statements)

References 36 publications

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“…PKC directly activates c-Raf, so these results are consistent with the known signaling antagonism of GW-5074. Similar results were obtained in the context of virus infection, as JCPyV infection could not be rescued by cotreating SVG-A cells with PMA and GW-5074 [150]. Taken together, these data support the hypothesis that GW-5074 disrupts MAPK-ERK signaling events needed to establish a productive JCPyV infection (Figure 4).…”

Section: Gw-5074: a Novel Jcpyv Inhibitor That Antagonizes Signaling ...supporting

confidence: 85%

“…Importantly, GW-5074 also inhibited long-term cell-to-cell spread of JCPyV when introduced after establishment of a productive infection. This result suggests that GW-5074 could be used to control PML in vivo, as most patients support uncontrolled virus replication before symptom onset [150].…”

Section: Gw-5074: a Novel Jcpyv Inhibitor That Antagonizes Signaling ...mentioning

confidence: 97%

“…GW-5074 was well-tolerated by both cell lines, as the 50% cytotoxic concentration (CC 50 ) associated with GW-5074 treatment was greater than 100 µM and 20 µM in SVG-A and NHA cells, respectively. Using these values, we calculated the minimum 50% selectivity index (SI 50 ), defined as the ratio between the CC 50 and IC 50 , associated with GW-5074 to be 11.8 in SVG-A cells and 20.2 in NHAs [150]. SI 50 values are important metrics in drug discovery, and an SI 50 greater than 10 is commonly considered to be an important starting point in drug development [7].…”

Section: Gw-5074: a Novel Jcpyv Inhibitor That Antagonizes Signaling ...mentioning

confidence: 99%

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An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy

Kaiserman

O’Hara

Haley

et al. 2023

IJMS

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Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by infection with JC Polyomavirus (JCPyV). Despite the identification of the disease and isolation of the causative pathogen over fifty years ago, no antiviral treatments or prophylactic vaccines exist. Disease onset is usually associated with immunosuppression, and current treatment guidelines are limited to restoring immune function. This review summarizes the drugs and small molecules that have been shown to inhibit JCPyV infection and spread. Paying attention to historical developments in the field, we discuss key steps of the virus lifecycle and antivirals known to inhibit each event. We review current obstacles in PML drug discovery, including the difficulties associated with compound penetrance into the central nervous system. We also summarize recent findings in our laboratory regarding the potent anti-JCPyV activity of a novel compound that antagonizes the virus-induced signaling events necessary to establish a productive infection. Understanding the current panel of antiviral compounds will help center the field for future drug discovery efforts.

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Section: Gw-5074: a Novel Jcpyv Inhibitor That Antagonizes Signaling ...supporting

confidence: 85%

Section: Gw-5074: a Novel Jcpyv Inhibitor That Antagonizes Signaling ...mentioning

confidence: 97%

Section: Gw-5074: a Novel Jcpyv Inhibitor That Antagonizes Signaling ...mentioning

confidence: 99%

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An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy

Kaiserman

O’Hara

Haley

et al. 2023

IJMS

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“…Maraviroc has been hypothesized to reduce the severity of PML-IRIS, but its clinical effectiveness has not been established [9]. Current research is exploring multiple drugs, including a promising compound called Oxindole GW-5074, which is still under trial [10].…”

Section: Discussionmentioning

confidence: 99%

Progressive Multifocal Leukoencephalopathy Mimicking a Cerebral Vasculitis Flare

Hussain¹,

Sunmboye²

2023

Cureus

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We report a case of a 68-year-old woman with a background of primary cerebral vasculitis, which was diagnosed two years ago. She appeared to have had a recurrence of her symptoms with new onset history of expressive dysphasia, right-sided upper limb weakness, and right-sided facial weakness during a rheumatology clinic visit. The patient was on maintenance azathioprine for her cerebral vasculitis at the time of presentation. She had received a total of 2 g of rituximab through intravenous infusion, with a twoweek interval between doses. Additionally, she had undergone intravenous cyclophosphamide treatment (15 mg/kg) following the standard vasculitis regimen for induction remission therapy, which was administered at the time of her diagnosis two years prior. Initial imaging on non-contrast computed tomography head after admission to the emergency department did not show any acute neurological findings. Further imaging studies revealed changes in the right parietotemporal white matter T2 hyperintensity with similar changes on the left frontal and left parietal lobes suggestive of progressive multifocal leukoencephalopathy (PML). A magnetic resonance imaging (MRI) of the brain conducted three months prior was found to be unremarkable. Cerebrospinal fluid (CSF) polymerase chain reaction (PCR) testing confirmed the presence of polyoma John Cunningham (JC) virus deoxyribonucleic acid (DNA). This case highlights that PML should be an important differential to consider in any immunocompromised patient who presents with new stroke-like features.

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The Oxindole GW-5074 Inhibits JC Polyomavirus Infection and Spread by Antagonizing the MAPK-ERK Signaling Pathway

Cited by 2 publications

References 36 publications

An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy

An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy

Progressive Multifocal Leukoencephalopathy Mimicking a Cerebral Vasculitis Flare

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