Walter
G. Hanel
1st
Year Graduate Student
Department:
Pathology
Graduate Program: Genetics
Advisor:
Ute Moll (rotating)
Abstract (rotation):
Preceptor: Dr. Sanford Simon, Department of Pathology, SBU
Title: Mechanism of anthrax lethal factor
inhibition by green tea products and antibiotics
Bacillus
anthracis is a gram-positive, spore forming bacteria which has been
recently used as a bioterrorism weapon. Bacillus anthracis secretes
a metalloproteinase, lethal factor (LF), which is hypothesized to be
the major cause of morbidity and mortality in humans infected with anthrax.
Thus, a major goal in the treatment and prevention of anthrax has been
to develop an effective inhibitor of LF to administer to patients upon
pre and post exposure to anthrax to prevent LF associated morbidity
and mortality. A series of compounds were investigated using three different
assays to determine the potency of inhibition and potential for future
drug development of these compounds: a FRET-based peptide substrate
cleavage assay, Western blotting for the prevention of MEK-2 degradation
in cell lysates as well as intact cells, and an MTS cell cytotoxicity
assay using human peripheral monocytes isolated from blood. Using thermorubin,
an antibiotic derived from the a thermophilic bacterium, and Minocycline,
a tetracycline antibiotic, it was shown that Thermorubin can inhibit
LF with a strong Ki (2.5uM) and prevent significant(80%) cell death
due to LF treatment, while Minocycline exhibited relatively weak activity
in the each of the assays tested. Among other compounds tested were
a series of polyphenol compounds derived from green tea. The compound
epigallocatechin gallate, as well as two O-methylated derivatives of
this compound, showed powerful inhibition in each of the assays tested.
These results reveal promise in future development of these compounds
in the treatment and prevention of Bacillus antracis lethal factor associated
morbidity and mortality.
Publications:
(MSTP-supported publications indicated with an *)
Kramer
JM., Hanel W., Shen F., Isik N., Malone J.P., Maitra
A., Sigurdson W., Swart D., Tocker J., Jin T., Gaffen SL. (2007). Cutting
Edge: Identification of a Pre-Ligand Assembly Domain (PLAD) and Ligand
Binding Site in the IL-17 Receptor. J Immunology.
179(10): 6379:83
Maitra
A., Shen F., Hanel W., Mossman K., Tocker J., Swart
D., Gaffen SL. (2007). Distinct functional motifs within the IL-17 receptor
regulate signal transduction and target gene expression. Proc
Natl Acad Sci. U.S.A. 104(18):7506-11
Tanner
MJ., Hanel W., Gaffen SL., Lin X. (2007). CARMA1 coiled-coil
domain is involved in the oligomerization and subcellular localization
of CARMA1 and is required for T-cell receptor-induced NF-kappaB activation.
J Biol Chem. 282(23):17141-7
