Antiviral activity of an isatin derivative via induction of PERK-Nrf2-mediated suppression of cap-independent translation.

TitleAntiviral activity of an isatin derivative via induction of PERK-Nrf2-mediated suppression of cap-independent translation.
Publication TypeJournal Article
Year of Publication2014
AuthorsZhang, 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
JournalACS Chem Biol
Volume9
Issue4
Pagination1015-24
Date Published2014 Apr 18
ISSN1554-8937
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.

DOI10.1021/cb400775z
Alternate JournalACS Chem. Biol.
PubMed ID24547890
Grant ListDC0190GP / / Canadian Institutes of Health Research / Canada