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GLUCOSE AND MANNOSE ANALOGS INHIBIT KSHV REPLICATION BY BLOCKING N-GLYCOSYLATION AND INDUCING THE UNFOLDED PROTEIN RESPONSE.

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 anti-cancer agent that is well-tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and SARS-Cov-2. Because 2-DG inhibits glycolysis and N-glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2-DG to 2-fluoro-deoxy-d-glucose (2-FDG), 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 down-regulation 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 PERK branch, particularly ATF4 and CHOP expression. Finally, we demonstrate that sugar analogs induce autophagy (a pro-survival 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 anti-enveloped virus target and sugar analogs such as 2-DG and the newly identified 2-DFM as antiviral drugs. This article is protected by copyright. All rights reserved.