Title | Antiviral activity of an isatin derivative via induction of PERK-Nrf2-mediated suppression of cap-independent translation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Zhang, HM, Dai, H, Hanson, PJ, Li, H, Guo, H, Ye, X, Hemida, MG, Wang, L, Tong, Y, Qiu, Y, Liu, S, Wang, F, Song, F, Zhang, B, Wang, J-G, Zhang, L-X, Yang, D |
Journal | ACS Chem Biol |
Volume | 9 |
Issue | 4 |
Pagination | 1015-24 |
Date Published | 2014 Apr 18 |
ISSN | 1554-8937 |
Abstract | We report here an isatin derivative 45 (ID45) against coxsackievirus B3 (CVB3) replication, which was synthesized based on a high-throughput screen of a unique natural product library. ID45 showed the most potent anti-CVB3 activity among the four synthesized compounds. Treatment of cells with ID45 before or after infection significantly reduced viral particle formation, resulting in protection of cells from virus-induced apoptosis. In addition, ID45 treatment caused remarkable up-regulation of glucose-regulated protein 78 (GRP78), a hallmark of endoplasmic reticulum (ER) stress and an indicator of enhanced cell viability. In identifying the ER stress response pathway induced by ID45, we found that ID45 activated PKR-like ER protein kinase (PERK) but failed to up-regulate eIF2α phosphorylation. Instead ID45 activated transcription factor Nrf2 (NF-E2-related factor-2), which is evidenced by its nuclear translocation and upregulation of its downstream target genes NQO1 (NAD(P)H quinone-oxidoreductase 1) and GCLM (glutamate-cysteine ligase, modifier subunit). This observation was further verified by using siRNAs of GRP78 or Nrf2, which blocked both the translocation of Nrf2 and up-regulation of its target genes, leading to aggressive viral replication and enhanced cell apoptosis. Finally, we found that ID45-induced up-regulation of NQO1 protected eIF4GI, a eukaryotic cap-dependent translation initiation factor, from cleavage by CVB3 protease and degradation by proteasomes. Taken together, our findings established that a novel antiviral mechanism of isatin derivative ID45 inhibits CVB3 replication by promoting cell survival through a PERK/Nrf2-dependent ER stress pathway, which benefits host cap-dependent translation but suppresses CVB3 cap-independent translation. |
DOI | 10.1021/cb400775z |
Alternate Journal | ACS Chem. Biol. |
PubMed ID | 24547890 |
Grant List | DC0190GP / / Canadian Institutes of Health Research / Canada |