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dc.contributor.author
Schlesinger, Mariana
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dc.contributor.author
McDonald, Christian
dc.contributor.author
Ahuja, Anuj
dc.contributor.author
Alvarez Canete, Carolina Alejandra
dc.contributor.author
Nuñez del Prado, Zelmira
dc.contributor.author
Naipauer, Julian
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dc.contributor.author
Lampidis, Theodore
dc.contributor.author
Mesri, Enrique Alfredo
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dc.date.available
2024-02-22T12:34:49Z
dc.date.issued
2023-01
dc.identifier.citation
Schlesinger, Mariana; McDonald, Christian; Ahuja, Anuj; Alvarez Canete, Carolina Alejandra; Nuñez del Prado, Zelmira; et al.; Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response; Wiley-liss, div John Wiley & Sons Inc.; Journal of Medical Virology; 95; 1; 1-2023; 1-16
dc.identifier.issn
0146-6615
dc.identifier.uri
http://hdl.handle.net/11336/228003
dc.description.abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS-associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2-deoxy- d-glucose (2-DG) is an anticancer agent that is well-tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2. Because 2-DG inhibits glycolysis and N-glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2-DG with 2-fluoro-deoxy- d-glucose, a glycolysis inhibitor, and 2-deoxy-fluoro- d-mannose (2-DFM), a specific N-glycosylation inhibitor. At doses similar to those clinically achievable with 2-DG, the three drugs impair KSHV replication and virion production in iSLK.219 cells via downregulation of viral structural glycoprotein expression (K8.1 and gB), being 2-DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2-DFM, we found that d-mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of N-glycosylation is the main antiviral target using d-mannose competition experiments. Suppression of N-glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV-induced inhibition of the protein kinase R-like endoplasmic reticulum kinase branch, particularly activating transcription factor 4 and C/EBP homologous protein expression. Finally, we demonstrate that sugar analogs induce autophagy (a prosurvival mechanism) and, thus, inhibit viral replication playing a protective role against KSHV-induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of N-glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2-DG and the newly identified 2-DFM as antiviral drugs.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Wiley-liss, div John Wiley & Sons Inc.
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
2-DEOXY-2-FLUORO-D-MANNOSE
dc.subject
2-DEOXY-D-GLUCOSE
dc.subject
2-FLUORO-DEOXY-D-GLUCOSE
dc.subject
KAPOSI'S SARCOMA HERPESVIRUS
dc.subject
SUGAR ANALOGS
dc.subject
UNFOLDED PROTEIN RESPONSE
dc.subject.classification
Virología
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2024-02-22T11:29:49Z
dc.journal.volume
95
dc.journal.number
1
dc.journal.pagination
1-16
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Schlesinger, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: McDonald, Christian. No especifíca;
dc.description.fil
Fil: Ahuja, Anuj. No especifíca;
dc.description.fil
Fil: Alvarez Canete, Carolina Alejandra. No especifíca;
dc.description.fil
Fil: Nuñez del Prado, Zelmira. No especifíca;
dc.description.fil
Fil: Naipauer, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
dc.description.fil
Fil: Lampidis, Theodore. University of Miami; Estados Unidos
dc.description.fil
Fil: Mesri, Enrique Alfredo. No especifíca;
dc.journal.title
Journal of Medical Virology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1002/jmv.28314
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