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dc.creatorSelaković, Života
dc.creatorTran, J.P.
dc.creatorKota, K.P.
dc.creatorLazić, Marija
dc.creatorRetterer, C.
dc.creatorBesh, R.
dc.creatorPanchal, R.G.
dc.creatorSoloveva, V.
dc.creatorSean, V.A.
dc.creatorJay, W.B.
dc.creatorPavić, A.
dc.creatorVerbić, Tatjana
dc.creatorVasiljević, Branka
dc.creatorKuehl, K.
dc.creatorDuplantier, A.J.
dc.creatorBavari, S.
dc.creatorMudhasani, R.
dc.creatorŠolaja, Bogdan A.
dc.date.accessioned2018-11-22T00:46:06Z
dc.date.available2018-11-22T00:46:06Z
dc.date.issued2019
dc.identifier.issn0223-5234
dc.identifier.urihttps://cherry.chem.bg.ac.rs/handle/123456789/360
dc.description.abstractEbola 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 SASen
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172008/RS//
dc.rightsrestrictedAccess
dc.sourceEuropean Journal of Medicinal Chemistry
dc.subjectDiazachrysene filovirus inhibitorsen
dc.subjectEbola virus entry inhibitorsen
dc.subjectLate endosomesen
dc.subjectLysosomotrophen
dc.subjectNaphthyridinesen
dc.titleSecond generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of actionen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractТран, Ј.П.; Кота, К.П.; Лазић, М.; Реттерер, Ц.; Бесх, Р.; Панцхал, Р.Г.; Вербић, Татјана; Шолаја, Богдан A.; Селаковић, Живота; Павић, A.; Јаy, W.Б.; Сеан, В.A.; Соловева, В.; Куехл, К.; Дуплантиер, A.Ј.; Бавари, С.; Мудхасани, Р.; Васиљевић, Б.;
dcterms.publisherElsevier
dc.citation.volume162
dc.citation.spage32
dc.citation.epage50
dc.identifier.wos000456762500003
dc.identifier.doi10.1016/j.ejmech.2018.10.061
dc.citation.other162: 32-50
dc.citation.rankaM21
dc.description.otherSupplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/2967]
dc.description.otherPeer-reviewed manuscript: [http://cherry.chem.bg.ac.rs/handle/123456789/2966]
dc.type.versionpublishedVersionen
dc.identifier.scopus2-s2.0-85056177974


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