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Antiviral Activity of an Isatin Derivative via Induction of PERK-Nrf2-mediated Suppression of Cap-Independent Translation

Antiviral Activity of an Isatin Derivative via Induction of PERK-Nrf2-mediated Suppression of Cap-Independent Translation

Huifang M Zhang, Huanqin Dai, Paul J Hanson, Huidong Li, Hui Guo, Xin Ye, Maged G Hemida, Luoqiang Wang, Yaojun Tong, Ye Qiu, Selina Liu, Fengping Wang, Fuhang Song, Buchang Zhang, Jian-Guo Wang, Li-Xin Zhang, etc.

ACS Chem Biol. 2014 Apr 18;9(4):1015-24.

PMID: 24547890

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4243674	ID45			Price

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