Antiviral Effects of Small Interfering RNA Simultaneously Inducing RNA Interference and Type 1 Interferon in Coxsackievirus Myocarditis

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2012 Apr 18

PMID 22508300

Citations 3

Authors

Jeonghyun Ahn

Ara Ko

Eun Jung Jun

Minah Won

Yoo Kyum Kim

Eun-Seon Ju

Eun Seok Jeon

Heuiran Lee

Affiliations

Soon will be listed here.

Abstract

Antiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5'-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus-specific siRNA with an empty hydroxyl group at the 5' end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus-specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3-specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus-specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases.

Citing Articles

The antiviral effect of jiadifenoic acids C against coxsackievirus B3.

Ge M, Wang H, Zhang G, Yu S, Li Y Acta Pharm Sin B. 2015; 4(4):277-83.

PMID: 26579396 PMC: 4629087. DOI: 10.1016/j.apsb.2014.06.008.

c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3.

Buskiewicz I, Koenig A, Roberts B, Russell J, Shi C, Lee S PLoS One. 2014; 9(5):e96156.

PMID: 24816846 PMC: 4015977. DOI: 10.1371/journal.pone.0096156.

Development of modified siRNA molecules incorporating 5-fluoro-2'-deoxyuridine residues to enhance cytotoxicity.

Wu S, Chen T, Gmeiner W, Chu E, Schmitz J Nucleic Acids Res. 2013; 41(8):4650-9.

PMID: 23449220 PMC: 3632118. DOI: 10.1093/nar/gkt120.

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