TY  - JOUR
AU  - Selaković, Zivota
AU  - Tran, Julie P.
AU  - Kota, Krishna P.
AU  - Lazić, Marija
AU  - Retterer, Cary
AU  - Besh, Robert
AU  - Panchal, Rekha G.
AU  - Soloveva, Veronica
AU  - Sean, Vantongreen A.
AU  - Jay, Wells B.
AU  - Pavić, Aleksandar
AU  - Verbić, Tatjana
AU  - Vasiljević, Branka
AU  - Kuehl, Kathleen
AU  - Duplantier, Allen J.
AU  - Bavari, Sina
AU  - Mudhasani, Rajini
AU  - Solaja, Bogdan A.
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1293
AB  - Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease.
PB  - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
T2  - European Journal of Medicinal Chemistry
T1  - Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action
EP  - 50
SP  - 32
VL  - 162
DO  - 10.1016/j.ejmech.2018.10.061
ER  - 

@article{
author = "Selaković, Zivota and Tran, Julie P. and Kota, Krishna P. and Lazić, Marija and Retterer, Cary and Besh, Robert and Panchal, Rekha G. and Soloveva, Veronica and Sean, Vantongreen A. and Jay, Wells B. and Pavić, Aleksandar and Verbić, Tatjana and Vasiljević, Branka and Kuehl, Kathleen and Duplantier, Allen J. and Bavari, Sina and Mudhasani, Rajini and Solaja, Bogdan A.",
year = "2019",
abstract = "Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease.",
publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux",
journal = "European Journal of Medicinal Chemistry",
title = "Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action",
pages = "50-32",
volume = "162",
doi = "10.1016/j.ejmech.2018.10.061"
}

Selaković, Z., Tran, J. P., Kota, K. P., Lazić, M., Retterer, C., Besh, R., Panchal, R. G., Soloveva, V., Sean, V. A., Jay, W. B., Pavić, A., Verbić, T., Vasiljević, B., Kuehl, K., Duplantier, A. J., Bavari, S., Mudhasani, R.,& Solaja, B. A.. (2019). Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action. in European Journal of Medicinal Chemistry
Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 162, 32-50.
https://doi.org/10.1016/j.ejmech.2018.10.061

Selaković Z, Tran JP, Kota KP, Lazić M, Retterer C, Besh R, Panchal RG, Soloveva V, Sean VA, Jay WB, Pavić A, Verbić T, Vasiljević B, Kuehl K, Duplantier AJ, Bavari S, Mudhasani R, Solaja BA. Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action. in European Journal of Medicinal Chemistry. 2019;162:32-50.
doi:10.1016/j.ejmech.2018.10.061 .

Selaković, Zivota, Tran, Julie P., Kota, Krishna P., Lazić, Marija, Retterer, Cary, Besh, Robert, Panchal, Rekha G., Soloveva, Veronica, Sean, Vantongreen A., Jay, Wells B., Pavić, Aleksandar, Verbić, Tatjana, Vasiljević, Branka, Kuehl, Kathleen, Duplantier, Allen J., Bavari, Sina, Mudhasani, Rajini, Solaja, Bogdan A., "Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action" in European Journal of Medicinal Chemistry, 162 (2019):32-50,
https://doi.org/10.1016/j.ejmech.2018.10.061 . .