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

Mariana Schlesinger, Christian McDonald, Anuj Ahuja, Carolina Alejandra Alvarez Canete, Zelmira Nuñez del Prado, Julian Naipauer, Theodore Lampidis, Enrique A. Mesri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere28314
JournalJournal of Medical Virology
Volume95
Issue number1
DOIs
StatePublished - Jan 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.

Keywords

  • 2-deoxy-2-fluoro-d-mannose
  • 2-deoxy-d-glucose
  • 2-fluoro-deoxy-d-glucose
  • Kaposi's sarcoma herpesvirus
  • sugar analogs
  • unfolded protein response

Fingerprint

Dive into the research topics of 'Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response'. Together they form a unique fingerprint.

Cite this