This is a proposal to understand, optimize and advance a lead candidate small molecule imino sugar forward for the management of human infection by either or both Ebola and Marburg viruses. We have identified lead imino sugars with nanomolar activity against multiple hemorrhagic fever viruses in vitro, and even in lethal models of mouse infection of Ebola and Marburg. Briefly, we achieved protection of up to 70% of the mice infected with lethal doses of either Ebola or Marburg viruses, with 25-50 milligram/kg dosing of the same imino sugar. Imino sugar N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide (hexyl-pival-DNJ, """"""""17028"""""""") and (2R,3R,4R,5S)-1-(6-(2,5-difluorophenoxy)hexyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (fluoro-hexyl-DNJ, """"""""11029"""""""") were similarly effective in both models, either as pre- or post-exposure treatment. However, only intraperitoneal (i.p.) administration studies were performed, and orally available compounds are preferred. But, DNJ containing imino sugars, such as our leads, have been associated with gastrointestinal (GI) distress, when taken orally, because of the inhibition of resident intestinal lumenal glucosidases. Therefore, """"""""pro-drug"""""""" modifications to the imino sugars, to improve compound oral bioavailability and reduce effects upon the GI track, will be carried out. Compounds with the best pre-clinical profile will then be tested for advanced in vitro and in vivo Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET), and advanced efficacy studies, against both Marburg and Ebola virus infections in multiple animal models. Taken together, although our two leads could be moved forward toward development as a parenterally administered drug, the preference is for an orally available medication devoid of GI glucosidase inhibitory activity. Thus, either the current lead or a second generation prodrug will be ready for IND enabling studies, with our commercialization partner, by the end of this project.

Public Health Relevance

Marburg and Ebola viruses cause deadly hemorrhagic infections. There are currently no antivirals that are effective in managing Ebola or Marburg infections of animals or people, and they are considered as possible biothreat agents. This proposal will develop a drug, which we showed has benefit in experimental animal models, intended to prevent human death following infection with either and possibly both of these viruses. Such a drug would be an important first.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104636-01
Application #
8474351
Study Section
Special Emphasis Panel (ZAI1-FDS-M (J1))
Program Officer
Tseng, Christopher K
Project Start
2013-06-15
Project End
2018-05-31
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$873,245
Indirect Cost
$210,395
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wang, Mengjun; Devarajan, Karthik; Singal, Amit G et al. (2016) The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 9:172-9
Ariza-Mateos, Ascensión; Díaz-Toledano, Rosa; Block, Timothy M et al. (2016) Geneticin Stabilizes the Open Conformation of the 5' Region of Hepatitis C Virus RNA and Inhibits Viral Replication. Antimicrob Agents Chemother 60:925-35
Guo, Fang; Han, Yanxing; Zhao, Xuesen et al. (2015) STING agonists induce an innate antiviral immune response against hepatitis B virus. Antimicrob Agents Chemother 59:1273-81
Liang, T Jake; Block, Timothy M; McMahon, Brian J et al. (2015) Present and future therapies of hepatitis B: From discovery to cure. Hepatology 62:1893-908
Yan, Ran; Zhao, Xuesen; Cai, Dawei et al. (2015) The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion. J Virol 89:9200-12
Zhao, Xuesen; Guo, Fang; Comunale, Mary Ann et al. (2015) Inhibition of endoplasmic reticulum-resident glucosidases impairs severe acute respiratory syndrome coronavirus and human coronavirus NL63 spike protein-mediated entry by altering the glycan processing of angiotensin I-converting enzyme 2. Antimicrob Agents Chemother 59:206-16
Chang, Jinhong; Block, Timothy M; Guo, Ju-Tao (2015) Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections. Antivir Ther 20:257-9
Block, Timothy M; Rawat, Siddhartha; Brosgart, Carol L (2015) Chronic hepatitis B: A wave of new therapies on the horizon. Antiviral Res 121:69-81
Zhao, Xuesen; Guo, Fang; Liu, Fei et al. (2014) Interferon induction of IFITM proteins promotes infection by human coronavirus OC43. Proc Natl Acad Sci U S A 111:6756-61
Guo, Fang; Zhao, Xuesen; Gill, Tina et al. (2014) An interferon-beta promoter reporter assay for high throughput identification of compounds against multiple RNA viruses. Antiviral Res 107:56-65

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