2. Academic Validation
  3. Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies

Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies

  • J Med Chem. 2018 Jul 26;61(14):6293-6307. doi: 10.1021/acs.jmedchem.8b00704.
Hu Liu 1,  Ye Tian 2 3,  Kyungae Lee 1,  Pranav Krishnan 2,  May Kwang-Mei Wang 2,  Sean Whelan 1,  Emily Mevers 4,  Veronica Soloveva 5,  Benjamin Dedic 2,  Xinyong Liu 3,  James M Cunningham 2 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunobiology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 2 Division of Hematology, Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , 44 West Culture Road , 250012 Jinan , Shandong , PR China.
  • 4 Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 5 United States Army Research Institute of Infectious Diseases , Fort Detrick , Maryland 21702 , United States.
PMID: 29920098 DOI: 10.1021/acs.jmedchem.8b00704
Abstract

Previous studies identified an adamantane dipeptide piperazine 3.47 that inhibits Ebola virus (EBOV) Infection by targeting the essential receptor Niemann-Pick C1 (NPC1). The physicochemical properties of 3.47 limit its potential for testing in vivo. Optimization by improving potency, reducing hydrophobicity, and replacing labile moieties identified 3.47 derivatives with improved in vitro ADME properties that are also highly active against EBOV Infection, including when tested in the presence of 50% normal human serum (NHS). In addition, 3A4 was identified as the major Cytochrome P450 isoform that metabolizes these compounds, and accordingly, mouse microsome stability was significantly improved when tested in the presence of the CYP3A4 inhibitor ritonavir that is approved for clinical use as a booster of anti-HIV drugs. Oral administration of the EBOV inhibitors with ritonavir resulted in a pharmacokinetic profile that supports a b.i.d. dosing regimen for efficacy studies in mice.

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