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

2012
Authors
Selaković, Života
Opsenica, Dejan

Eaton, Brett
Retterer, Cary
Bavari, Sina

Burnett, James C.
Šolaja, Bogdan

Panchal, Rekha G.
Article (Published version)
Metadata
Show full item recordAbstract
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.
Keywords:
filovirus / Ebola virus / Marburg virus / antiviral / diazachrysene / inhibitory efficacy / toxicity / small moleculeSource:
Viruses-Basel, 2012, 4, 8, 1279-1288Publisher:
- MDPI
Funding / projects:
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
- Frederick National Laboratory for Cancer Research, National Institutes of Health (US) [HHSN261200800001E]
- Joint Science and Technology Office [TMTI_00048_RD_T]
DOI: 10.3390/v4081279
ISSN: 1999-4915
PubMed: 23012625
WoS: 000308213000007
Scopus: 2-s2.0-84868605426
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IHTMTY - 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 . .