Development of an effective therapy against post-exposure Anthrax. Anthrax is an infectious disease caused by the bacterium Bacillus anthracis. This rod shaped bacterium infects humans through the respiratory system, skin, or digestive tract. Dependent upon the entry route into the human body, Anthrax can be highly lethal. Although cutaneous Anthrax is rarely lethal, inhalation Anthrax is dangerous and usually fatal. Upon inhalation, the Anthrax spores adhere to the alveolar macrophages and germinate. Bacteria migrate to the lymph node, in which they rapidly multiply and excrete a tripartite exotoxin comprised of protective antigen (PA), lethal factor (LF, a Zn2+ dependant metalloproteinase) and calmodulin-activated edema factor adenylate cyclase (EF). The combined actions of these proteins constitute the Anthrax toxin which induces cell death particularly in macrophages by the action of LF. Once in the cytosol, LF is able to cleave several members of the MAPKK family near their N-terminus preventing interaction with, and phosphorylation of, downstream MAPKs, thereby inhibiting one or more signaling pathways. High liter of the bacteria and concomitant high level of LF in the blood stream will lead to the death of the host organism. Therefore, the developments of treatments that include a combination of antibiotics with orally active, potent, safe and selective LF inhibitors should provide an efficacious countermeasure to post-exposure Anthrax. Our three specific aims are: (I) To increase, through iterative optimizations selectivity, potency and drug-likeness of selected LF inhibitors. (II) To perform in vitro and in cell toxicity studies to refine hits and identify drug-like inhibitor(s) of LF for subsequent in vivo studies. (Ill) To perform in vivo efficacy evaluations and necessary formulation, PK and toxicity studies. Relevance Inhalation Anthrax is the most deadly form of this disease. After infection, Anthrax spores are engulfed by alveolar macrophages where germinate to generate the bacteria, which spread through the lymph nodes to the bloodstream, eventually leading to systemic fatal shock presumably due to the action of the secreted Anthrax toxin. LF (lethal factor) is a key component of the secreted toxin and plays a major role in inducing apoptosis (cell-death) of macrophages by cleaving the specific human cell signaling proteins. Our plan is to develop potent, safe, selective and orally active compounds that inhibit LF, which should prevent macrophage cell-death and promote termination of the disease. Such inhibitors will be tested as single agents and in combination with antibiotics, in order to develop the most efficacious post-exposure therapy that should facilitate and assure the recovery of patients who harbor the disease. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI070494-03
Application #
7480298
Study Section
Special Emphasis Panel (ZAI1-LR-M (M1))
Program Officer
Xu, Zuoyu
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$1,147,755
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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