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 mu M +/- 0.13 mu M and 2.76 mu M +/- 0.21 mu M 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.
TY - JOUR
AU - Selaković, Života
AU - Opsenica, Dejan
AU - Eaton, Brett
AU - Retterer, Cary
AU - Bavari, Sina
AU - Burnett, James C.
AU - Šolaja, Bogdan
AU - Panchal, Rekha G.
PY - 2012
UR - https://cer.ihtm.bg.ac.rs/handle/123456789/1109
AB - 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 mu M +/- 0.13 mu M and 2.76 mu M +/- 0.21 mu M 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.
PB - MDPI
T2 - Viruses-Basel
T1 - A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor
VL - 4
IS - 8
SP - 1279
EP - 1288
DO - 10.3390/v4081279
ER -
@article{
author = "Selaković, Života and Opsenica, Dejan and Eaton, Brett and Retterer, Cary and Bavari, Sina and Burnett, James C. and Šolaja, Bogdan and Panchal, Rekha G.",
year = "2012",
abstract = "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 mu M +/- 0.13 mu M and 2.76 mu M +/- 0.21 mu M 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.",
publisher = "MDPI",
journal = "Viruses-Basel",
title = "A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor",
volume = "4",
number = "8",
pages = "1279-1288",
doi = "10.3390/v4081279"
}
Selaković, Ž., Opsenica, D., Eaton, B., Retterer, C., Bavari, S., Burnett, J. C., Šolaja, B.,& Panchal, R. G.. (2012). A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor. in Viruses-Basel
MDPI., 4(8), 1279-1288.
https://doi.org/10.3390/v4081279
Selaković Ž, Opsenica D, Eaton B, Retterer C, Bavari S, Burnett JC, Šolaja B, Panchal RG. A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor. in Viruses-Basel. 2012;4(8):1279-1288.
doi:10.3390/v4081279 .
Selaković, Života, Opsenica, Dejan, Eaton, Brett, Retterer, Cary, Bavari, Sina, Burnett, James C., Šolaja, Bogdan, Panchal, Rekha G., "A Limited Structural Modification Results in a Significantly More Efficacious Diazachrysene-Based Filovirus Inhibitor" in Viruses-Basel, 4, no. 8 (2012):1279-1288,
https://doi.org/10.3390/v4081279 . .
