Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action
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2019
Authors
Selaković, ŽivotaTran, J.P.
Kota, K.P.
Lazić, Marija
Retterer, C.
Besh, R.
Panchal, R.G.
Soloveva, V.
Sean, V.A.
Jay, W.B.
Pavić, A.
Verbić, Tatjana
Vasiljević, Branka
Kuehl, K.
Duplantier, A.J.
Bavari, S.
Mudhasani, R.
Šolaja, Bogdan A.
Article (Published version)
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Show full item recordAbstract
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, com...pounds 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. © 2018 Elsevier Masson SAS
Keywords:
Diazachrysene filovirus inhibitors / Ebola virus entry inhibitors / Late endosomes / Lysosomotroph / NaphthyridinesSource:
European Journal of Medicinal Chemistry, 2019, 162, 32-50Publisher:
- Elsevier
Funding / projects:
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-MESTD-Basic Research (BR or ON)-172008)
Note:
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/2967
- Peer-reviewed manuscript: http://cherry.chem.bg.ac.rs/handle/123456789/2966
DOI: 10.1016/j.ejmech.2018.10.061
ISSN: 0223-5234
WoS: 000456762500003
Scopus: 2-s2.0-85056177974
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Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Selaković, Života AU - Tran, J.P. AU - Kota, K.P. AU - Lazić, Marija AU - Retterer, C. AU - Besh, R. AU - Panchal, R.G. AU - Soloveva, V. AU - Sean, V.A. AU - Jay, W.B. AU - Pavić, A. AU - Verbić, Tatjana AU - Vasiljević, Branka AU - Kuehl, K. AU - Duplantier, A.J. AU - Bavari, S. AU - Mudhasani, R. AU - Šolaja, Bogdan A. PY - 2019 UR - https://cherry.chem.bg.ac.rs/handle/123456789/360 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. © 2018 Elsevier Masson SAS T2 - European Journal of Medicinal Chemistry T1 - Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action VL - 162 SP - 32 EP - 50 DO - 10.1016/j.ejmech.2018.10.061 ER -
@article{ author = "Selaković, Života and Tran, J.P. and Kota, K.P. and Lazić, Marija and Retterer, C. and Besh, R. and Panchal, R.G. and Soloveva, V. and Sean, V.A. and Jay, W.B. and Pavić, A. and Verbić, Tatjana and Vasiljević, Branka and Kuehl, K. and Duplantier, A.J. and Bavari, S. and Mudhasani, R. and Šolaja, 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. © 2018 Elsevier Masson SAS", journal = "European Journal of Medicinal Chemistry", title = "Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action", volume = "162", pages = "32-50", doi = "10.1016/j.ejmech.2018.10.061" }
Selaković, Ž., 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.,& Šolaja, B. A.. (2019). Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action. in European Journal of Medicinal Chemistry, 162, 32-50. https://doi.org/10.1016/j.ejmech.2018.10.061
Selaković Ž, Tran J, Kota K, Lazić M, Retterer C, Besh R, Panchal R, Soloveva V, Sean V, Jay W, Pavić A, Verbić T, Vasiljević B, Kuehl K, Duplantier A, Bavari S, Mudhasani R, Šolaja 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, Života, Tran, J.P., Kota, K.P., Lazić, Marija, Retterer, C., Besh, R., Panchal, R.G., Soloveva, V., Sean, V.A., Jay, W.B., Pavić, A., Verbić, Tatjana, Vasiljević, Branka, Kuehl, K., Duplantier, A.J., Bavari, S., Mudhasani, R., Šolaja, 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 . .