A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor

Viruses

Života Selaković³  Dejan Opsenica²  Brett Eaton⁴  Cary Retterer⁴  Sina Bavari⁴  James C. Burnett¹  Bogdan A. Šolaja³ 

[1] SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, MD 21702, USAInstitute of Chemistry, Technology, and Metallurgy, University of Belgrade, Belgrade 11000, Serbia;University of Belgrade, Studentski trg 16, P.O. Box 51, Belgrade 11158, Serbia;United States Army Medical Research Institute of Institute of Infectious Diseases, Fort Detrick, 1425 Porter Street, Frederick, MD 21702, USA;

关键词: filovirus;    Ebola virus;    Marburg virus;    antiviral;    diazachrysene;    inhibitory efficacy;    toxicity;    small molecule;   

DOI  :  10.3390/v4081279

来源: mdpi

【 摘 要 】

Ebola (EBOV) and Marburg (MARV) filoviruses are highly infectious pathogens causing deadly hemorrhagic fever in humans and non-human primates. Promising vaccine candidates providing immunity against filoviruses have been reported. However, the sporadic nature and swift progression of filovirus disease underlines the need for the development of small molecule therapeutics providing immediate antiviral effects. Herein we describe a brief structural exploration of two previously reported diazachrysene (DAAC)-based EBOV inhibitors. Specifically, three analogs were prepared to examine how slight substituent modifications would affect inhibitory efficacy and inhibitor-mediated toxicity during not only EBOV, but also MARV cellular infection. Of the three analogs, one was highly efficacious, providing IC₅₀ values of 0.696 µM ± 0.13 µM and 2.76 µM ± 0.21 µM against EBOV and MARV infection, respectively, with little or no associated cellular toxicity. Overall, the structure-activity and structure-toxicity results from this study provide a framework for the future development of DAAC-based filovirus inhibitors that will be both active and non-toxic in vivo.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.