{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:15:11Z","timestamp":1788909311202,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Kaposi's sarcoma\u2010associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV\/AIDS\u2010associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2\u2010deoxy\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010glucose (2\u2010DG) is an anticancer agent that is well\u2010tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2.\u00a0Because 2\u2010DG inhibits glycolysis and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2\u2010DG with\u00a02\u2010fluoro\u2010deoxy\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010glucose, a glycolysis inhibitor, and 2\u2010deoxy\u2010fluoro\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010mannose (2\u2010DFM), a specific\n                    <jats:italic>N<\/jats:italic>\n                    \u2010glycosylation inhibitor. At doses similar to those clinically achievable with 2\u2010DG, 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\u2010DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2\u2010DFM, we found that\n                    <jats:sc>d<\/jats:sc>\n                    \u2010mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010glycosylation is the main antiviral target using\n                    <jats:sc>d<\/jats:sc>\n                    \u2010mannose competition experiments. Suppression of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV\u2010induced inhibition of the protein kinase R\u2010like endoplasmic reticulum kinase\u00a0branch, particularly activating\u00a0transcription factor 4\u00a0and 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\u2010induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2\u2010DG and the newly identified 2\u2010DFM as antiviral drugs.\n                  <\/jats:p>","DOI":"10.1002\/jmv.28314","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T23:31:30Z","timestamp":1668555090000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Glucose and mannose analogs inhibit KSHV replication by blocking\n                    <i>N<\/i>\n                    \u2010glycosylation and inducing the unfolded protein response"],"prefix":"10.1002","volume":"95","author":[{"given":"Mariana","family":"Schlesinger","sequence":"first","affiliation":[{"name":"Tumor Biology Program Sylvester Comprehensive Cancer Center  Miami Florida USA"},{"name":"Department of 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Comprehensive Cancer Center  Miami Florida USA"},{"name":"Department of Microbiology and Immunology Miami Center for AIDS Research  MIAMI Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelmira","family":"Nu\u00f1ez del Prado","sequence":"additional","affiliation":[{"name":"Tumor Biology Program Sylvester Comprehensive Cancer Center  Miami Florida USA"},{"name":"Department of Microbiology and Immunology Miami Center for AIDS Research  MIAMI Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6842-6815","authenticated-orcid":false,"given":"Julian","family":"Naipauer","sequence":"additional","affiliation":[{"name":"Tumor Biology Program Sylvester Comprehensive Cancer Center  Miami Florida USA"},{"name":"Department of Microbiology and Immunology Miami Center for AIDS Research  MIAMI Florida USA"},{"name":"UM\u2010CFAR\/SCCC Argentina Consortium for AIDS Malignancies  Miami Florida USA"},{"name":"Instituto 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