Potential Ebola therapies identifi ed using high throughput pheno | 903
Journal of Antivirals & Antiretrovirals

Journal of Antivirals & Antiretrovirals
Open Access

ISSN: 1948-5964

+44 1300 500008

Potential Ebola therapies identifi ed using high throughput phenotypic screening of drugs and combinations

International Conference and Exhibition on VIROLOGY

5-7 September 2011 Baltimore, USA

Gene Olinger, B.G. Hoffstrom1, A. Stossel, C. Scully, J. Brannan, D. Julias, C. Lear, J. Leh�r, L. M. Johansen and L. Hensley

Scientific Tracks Abstracts: JAA

Abstract :

To date, Ebola lacks licensed vaccines or therapeutics for prophylaxis or post-exposure treatment. Phenotypic screening of approved drugs can discover therapies that can be quickly deployed, and which oft en target host factors. We assembled a library of about 3,000 approved drugs and biologically active molecules, and tested them at multiple concentrations for antiviral activity using VERO cells infected with an engineered GFP-expressing Ebola virus. Hits were selected using both activity measurements and clinical safety information, and comparisons between agents targeting the same protein were used to distinguish on- vs. off -target eff ects. We identifi ed ~130 potential therapies with selective antiviral activity on ~50 distinct mechanistic classes. Th irty compounds were prioritized for active combination screening which resulted in 435 unique pair-wise combinations. Many of the antiviral activities discovered involve host cell mechanisms with previously unknown relevance to fi lovirus infection, including estrogen receptor antagonists and calcium channel blockers. We identifi ed many synergistic or additive drug combinations, fi ve of which yielded over tenfold increases of potency over the single agent activity. Results in a mouse Ebola infection model confi rm that many of the mechanistic classes identifi ed have protective antiviral eff ects including estrogen receptor antagonists, calcium channel blockers and drugs with CNS indications. Th e drugs identifi ed show translation in animal models supporting the potential of developing these drugs for clinical use. In addition to discovering novel viral-host mechanisms, testing these drugs in combination has revealed unforeseen drug synergies that can substantially improve therapeutic selectivity and limit the emergence of resistance.

Biography :

Dr. Olinger is the principle investigator of several projects focused on the development of countermeasures against highly lethal viral hemorrhagic fever viruses (VHFV). His team works on the development of vaccines and therapeutics for VHFV, specifi cally Ebola and Marburg viruses. Dr. Olinger has a Ph.D. in immunology and virology from Rush University in Chicago, IL and was awarded a post-doctoral research fellow with the National Research Council working at USAMRIID. Dr. Olinger has served as a subject matter expert for multiple DOD and Federal panels related to biodefense and serves as an NIH review for HIV SBIR & STTR research.