Beta-cyclodextrin derivatives that inhibit anthrax lethal toxin.
Recently, we demonstrated that simultaneous blocking of bacterial growth by antibiotics and inhibition of anthrax toxin action with antibodies against protective antigen were beneficial for the treatment of anthrax. The present study examined the hypothesis that blocking the pore formed by protective antigen can inhibit the action of anthrax toxin. The potential inhibitors were chosen by a structure-based design using beta-cyclodextrin as the starting molecule. Several beta-cyclodextrin derivatives were evaluated for their ability to protect RAW 264.7 cells from the action of anthrax lethal toxin. Per-substituted aminoalkyl derivatives displayed inhibitory activity and were protective against anthrax lethal toxin action at low micromolar concentrations. These results provide the basis for a structure-based drug discovery program, with the goal of identifying new drug candidates for anthrax treatment.
Karginov
Vladimir A
VA
Innovative Biologics, Inc., 10900 University Blvd., Manassas, VA 20110, USA. vak@innovbio.com
Yohannes
Adiamseged
A
Robinson
Tanisha M
TM
Fahmi
Nour Eddine
NE
Alibek
Kenneth
K
Hecht
Sidney M
SM
D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D051379:Mice; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000494:pharmacology*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D047392:beta-Cyclodextrins; C031215:betadex