Resistance Evolution against Host-directed Antiviral Agents: Buffalopox Virus Switches to Use p38-ϒ under Long-term Selective Pressure of an Inhibitor Targeting p38-α

Chander, Yogesh; Kumar, Ram; Verma, Ashu; Khandelwal, Nitin; Nagori, Himanshu; Singh, Namita Ashish; Sharma, Shalini; Pal, Yash; Puvar, Apurvasinh; Pandit, Rameshchandra; Shukla, Nitin; Chavada, Priyank; Tripathi, Bhupendra Nath; Barua, Sanjay; Kumar, Naveen

doi:10.1093/molbev/msac177

Cited by 13 publications

(14 citation statements)

References 73 publications

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“…Moreover, apoptosis assays determined by ow cytometry showed that hypoxia reduced chemosensitivity of glioma cells to TMZ, while drug tolerance induced by hypoxia was rescued by SB239063, a p38/MAPK inhibitor (Figs. 6E-H) (42). Furthermore, analysis of TCGA datasets revealed p38α (MAPK14) was upregulated in glioma samples compared to non-tumor samples (Fig.…”

Section: Hypoxia Induces Tmz Resistance In a P38α/mapk-dependent Mannermentioning

confidence: 83%

Targeting ARNT attenuates Chemoresistance Through Destabilizing p38α-MAPK Signaling in Glioblastoma

Alafate,

Lv,

Zheng

et al. 2024

Preprint

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Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.

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Section: Hypoxia Induces Tmz Resistance In a P38α/mapk-dependent Mannermentioning

confidence: 83%

Targeting ARNT attenuates Chemoresistance Through Destabilizing p38α-MAPK Signaling in Glioblastoma

Alafate,

Lv,

Zheng

et al. 2024

Preprint

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“…In our study, hesperetin‐resistant BPXV mutants were not observed even when the virus was sequentially cultured 40 times in the presence of hesperetin. This seems to be due to the low genetic variability of the host factor (eIF4E), thereby imposing a higher genetic barrier to the generation of resistant viruses 33,36,53 …”

Section: Discussionmentioning

confidence: 99%

“…This seems to be due to the low genetic variability of the host factor (eIF4E), thereby imposing a higher genetic barrier to the generation of resistant viruses. 33,36,53 Since hesperetin can alter cell metabolism, its long-term use could eventually result in cytotoxicity. Therefore, its further validation, long-term in vivo efficacy, and clinical trials will be essential before actually introducing it from research into clinical settings.…”

Section: Discussionmentioning

confidence: 99%

“…The in vitro interaction between BPXV mRNA and eIF4E was performed using the RNA-IP assay as described previously by our group. 39 Briefly, confluent monolayers of Vero cells in triplicates were infected with BPXV at 5 MOI for 1 h, followed by washing with PBS. Cells were supplemented with fresh DMEM, and hesperetin or DMSO was added at 3 hpi.…”

Section: In Ovo Antiviral Efficacymentioning

confidence: 99%

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Hesperetin blocks poxvirus replication with a low tendency to select for drug‐resistant viral variants

Verma,

Dedar,

Kumar

et al. 2024

Journal of Medical Virology

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In this study, we demonstrated the antiviral efficacy of hesperetin against multiple poxviruses, including buffalopox virus (BPXV), vaccinia virus (VACV), and lumpy skin disease virus (LSDV). The time‐of‐addition and virus step‐specific assays indicated that hesperetin reduces the levels of viral DNA, mRNA, and proteins in the target cells. Further, by immunoprecipitation (IP) of the viral RNA from BPXV‐infected Vero cells and a cell‐free RNA‐IP assay, we demonstrated that hesperetin‐induced reduction in BPXV protein synthesis is also consistent with diminished interaction between eukaryotic translation initiation factor eIF4E and the 5′ cap of viral mRNA. Molecular docking and MD simulation studies were also consistent with the binding of hesperetin to the cap‐binding pocket of eIF4E, adopting a conformation similar to m7GTP binding. Furthermore, in a BPXV egg infection model, hesperetin was shown to suppress the development of pock lesions on the chorioallantoic membrane and associated mortality in the chicken embryos. Most importantly, long‐term culture of BPXV in the presence of hesperetin did not induce the generation of drug‐resistant viral mutants. In conclusion, we, for the first time, demonstrated the antiviral activity of hesperetin against multiple poxviruses, besides providing some insights into its potential mechanisms of action.

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“…However, a complete resistance could not be achieved. Previous study by our group on buffalopox virus suggests that virus switches to use alternate cellular factor (p38-α to p38-γ) upon long-term restricted availability of the inhibitor targeting p38-α (Chander et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

p38-MAPK is prerequisite for the synthesis of SARS-CoV-2 protein

Mittal,

Khandelwal,

Chander

et al. 2023

Preprint

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The inhibition of p38 mitogen-activated protein kinase (p38-MAPK) by small molecule chemical inhibitors was previously shown to impair severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) replication, however, mechanisms underlying antiviral activity remains unexplored. In this study, reduced growth of SARS-CoV-2 in p38-α knockout Vero cells, together with enhanced viral yield in cells transfected with construct expressing p38α, suggested that p38-MAPK is essential for the propagation of SARS-CoV-2. The SARS-CoV-2 was also shown to induce phosphorylation (activation) of p38, at time when transcription/translational activities are considered to be at the peak levels. Further, we demonstrated that p38 supports viral RNA/protein synthesis without affecting viral attachment, entry, and budding in the target cells. In addition, we demonstrated that long-term culture of SARS-CoV-2 in the presence of p38 inhibitor SB203580 does not easily select resistant viral mutants. In conclusion, we provide mechanistic insights on the regulation of SARS-CoV-2 replication by p38 MAPK.

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Resistance Evolution against Host-directed Antiviral Agents: Buffalopox Virus Switches to Use p38-ϒ under Long-term Selective Pressure of an Inhibitor Targeting p38-α

Cited by 13 publications

References 73 publications

Targeting ARNT attenuates Chemoresistance Through Destabilizing p38α-MAPK Signaling in Glioblastoma

Targeting ARNT attenuates Chemoresistance Through Destabilizing p38α-MAPK Signaling in Glioblastoma

Hesperetin blocks poxvirus replication with a low tendency to select for drug‐resistant viral variants

p38-MAPK is prerequisite for the synthesis of SARS-CoV-2 protein

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