Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action
Authors
Selaković, ZivotaTran, 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.
Article (Accepted Version)
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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.
Keywords:
Naphthyridines / Lysosomotroph / Late endosomes / Ebola virus entry inhibitors / Diazachrysene filovirus inhibitorsSource:
European Journal of Medicinal Chemistry, 2019, 162, 32-50Publisher:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Funding / projects:
- National Institute of Allergy and Infectious Diseases [5-U01AI082051-02]
- Department of Defense Chemical Biological Defense Program through the Defense Threat Reduction Agency under United States Army Medical Research Institute of Infectious Diseases [13255634]
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-MESTD-Basic Research (BR or ON)-172008)
- Serbian Academy of Sciences and Arts
DOI: 10.1016/j.ejmech.2018.10.061
ISSN: 0223-5234
PubMed: 30408747
WoS: 000456762500003
Scopus: 2-s2.0-85056177974
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - 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 . .