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

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.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

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 JG,Zhang LX,Yang D

doi

10.1021/cb400775z

subject

Has Abstract

pub_date

2014-04-18 00:00:00

pages

1015-24

issue

4

eissn

1554-8929

issn

1554-8937

journal_volume

9

pub_type

杂志文章

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