Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response

• Autores: Schlesinger, Mariana; McDonald, Christian; Ahuja, Anuj; Alvarez Canete, Carolina Alejandra; Nuñez del Prado, Zelmira; Naipauer, Julian; Lampidis, Theodore; Mesri, Enrique Alfredo
• Año de publicación: 2023
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: 2-DEOXY-2-FLUORO-D-MANNOSE; 2-DEOXY-D-GLUCOSE; 2-FLUORO-DEOXY-D-GLUCOSE; KAPOSI'S SARCOMA HERPESVIRUS; SUGAR ANALOGS; UNFOLDED PROTEIN RESPONSE
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Schlesinger, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: McDonald, Christian. No especifíca;
Fil: Ahuja, Anuj. No especifíca;
Fil: Alvarez Canete, Carolina Alejandra. No especifíca;
Fil: Nuñez del Prado, Zelmira. No especifíca;
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
Fil: Lampidis, Theodore. University of Miami; Estados Unidos
Fil: Mesri, Enrique Alfredo. No especifíca;