2. Academic Validation
  3. Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action

Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action

  • Eur J Med Chem. 2019 Jan 15:162:32-50. doi: 10.1016/j.ejmech.2018.10.061.
Života Selaković 1,  Julie P Tran 2,  Krishna P Kota 2,  Marija Lazić 1,  Cary Retterer 2,  Robert Besch 2,  Rekha G Panchal 2,  Veronica Soloveva 2,  Vantongreen A Sean 2,  Wells B Jay 2,  Aleksandar Pavić 3,  Tatjana Verbić 1,  Branka Vasiljević 3,  Kathleen Kuehl 2,  Allen J Duplantier 2,  Sina Bavari 2,  Rajini Mudhasani 4,  Bogdan A Šolaja 5
Affiliations

Affiliations

  • 1 University of Belgrade, Faculty of Chemistry, Studentski trg 12-16, P.O. Box 51, 11158, Belgrade, Serbia.
  • 2 Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, United States.
  • 3 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
  • 4 Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, United States; Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, United States. Electronic address: [email protected].
  • 5 University of Belgrade, Faculty of Chemistry, Studentski trg 12-16, P.O. Box 51, 11158, Belgrade, Serbia; Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11158, Belgrade, Serbia. Electronic address: [email protected].
PMID: 30408747 DOI: 10.1016/j.ejmech.2018.10.061
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.

Keywords

Diazachrysene filovirus inhibitors; Ebola virus entry inhibitors; Late endosomes; Lysosomotroph; Naphthyridines.

Figures