Identification of small molecule inhibitors of anthrax lethal factor.
The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K(i) values in the 0.5-5 microM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.
Panchal
Rekha G
RG
Developmental Therapeutics Program, NCI Frederick, Frederick, Maryland 21702-1201, USA. panchal@dtpax2.ncifcrf.gov
Hermone
Ann R
AR
Nguyen
Tam Luong
TL
Wong
Thiang Yian
TY
Schwarzenbacher
Robert
R
Schmidt
James
J
Lane
Douglas
D
McGrath
Connor
C
Turk
Benjamin E
BE
Burnett
James
J
Aman
M Javad
MJ
Little
Stephen
S
Sausville
Edward A
EA
Zaharevitz
Daniel W
DW
Cantley
Lewis C
LC
Liddington
Robert C
RC
Gussio
Rick
R
Bavari
Sina
S
D000818:Animals; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin