Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening.
Anthrax lethal factor (LF) is a key virulence factor of anthrax lethal toxin. We screened a chemolibrary of 10,000 drug-like molecules for their ability to inhibit LF and identified 18 novel small molecules with potent LF inhibitory activity. Three additional LF inhibitors were identified through further structure-activity relationship (SAR) analysis. All 21 compounds inhibited LF with an IC50 range of 0.8 to 11 muM, utilizing mixed-mode competitive inhibition. An evaluation of inhibitory activity against a range of unrelated proteases showed relatively high specificity for LF. Furthermore, pharmacophore modeling of these compounds showed a high degree of similarity to the model published by Panchal et al. (Nat. Struct. Mol. Biol. 2004, 11, 67-72), indicating that the conformational features of these inhibitors are structurally compatible with the steric constraints of the substrate-binding pocket. These novel LF inhibitors and the structural scaffolds identified as important for inhibitory activity represent promising leads to pursue for further LF inhibitor development.
Schepetkin
Igor A
IA
Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, USA.
Khlebnikov
Andrei I
AI
Kirpotina
Liliya N
LN
Quinn
Mark T
MT
D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; C030325:anthrax toxin