Inhibition of Coxsackievirus B3 in Cell Cultures and in Mice by Peptide-Conjugated Morpholino Oligomers Targeting the Internal Ribosome Entry Site
-
Published:2006-12
Issue:23
Volume:80
Page:11510-11519
-
ISSN:0022-538X
-
Container-title:Journal of Virology
-
language:en
-
Short-container-title:J Virol
Author:
Yuan Ji1, Stein David A.2, Lim Travis1, Qiu Dexin1, Coughlin Shaun1, Liu Zhen1, Wang Yinjing1, Blouch Robert2, Moulton Hong M.2, Iversen Patrick L.2, Yang Decheng1
Affiliation:
1. The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada 2. AVI BioPharma, Inc., Corvallis, Oregon
Abstract
ABSTRACT
Coxsackievirus B3 (CVB3) is a primary cause of viral myocarditis, yet no effective therapeutic against CVB3 is available. Nucleic acid-based interventional strategies against various viruses, including CVB3, have shown promise experimentally, but limited stability and inefficient delivery in vivo remain as obstacles to their potential as therapeutics. We employed phosphorodiamidate morpholino oligomers (PMO) conjugated to a cell-penetrating arginine-rich peptide, P007 (to form PPMO), to address these issues. Eight CVB3-specific PPMO were evaluated with HeLa cells and HL-1 cardiomyocytes in culture and in a murine infection model. One of the PPMO (PPMO-6), designed to target a sequence in the 3′ portion of the CVB3 internal ribosomal entry site, was found to be especially potent against CVB3. Treatment of cells with PPMO-6 prior to CVB3 infection produced an approximately 3-log
10
decrease in viral titer and largely protected cells from a virus-induced cytopathic effect. A similar antiviral effect was observed when PPMO-6 treatment began shortly after the virus infection period. A/J mice receiving intravenous administration of PPMO-6 once prior to and once after CVB3 infection showed an ∼2-log
10
-decreased viral titer in the myocardium at 7 days postinfection and a significantly decreased level of cardiac tissue damage, compared to the controls. Thus, PPMO-6 provided potent inhibition of CVB3 amplification both in cell cultures and in vivo and appears worthy of further evaluation as a candidate for clinical development.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
Reference38 articles.
1. Boucek, M. M., A. Faro, R. J. Novick, L. E. Bennett, B. M. Keck, and J. D. Hosenpud. 2001. The registry of the International Society for Heart and Lung Transplantation: fourth official pediatric report—2000. J. Heart Lung Transplant.20:39-52. 2. Brown, D. A., S. H. Kang, S. M. Gryaznov, L. DeDionisio, O. Heidenreich, S. Sullivan, X. Xu, and M. I. Nerenberg. 1994. Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J. Biol. Chem.269:26801-26805. 3. Cheung, P., M. Zhang, J. Yuan, D. Chau, B. Yanagawa, B. McManus, and D. Yang. 2002. Specific interactions of HeLa cell proteins with Coxsackievirus B3 RNA: La autoantigen binds differentially to multiple sites within the 5′ untranslated region. Virus Res.90:23-36. 4. Chow, L. H., K. W. Beisel, and B. M. McManus. 1992. Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab. Investig.66:24-31. 5. Chow, L. H., C. J. Gauntt, and B. M. McManus. 1991. Differential effects of myocarditic variants of Coxsackievirus B3 in inbred mice. A pathologic characterization of heart tissue damage. Lab. Investig.64:55-64.
Cited by
62 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|