Search for cyclodextrin-based inhibitors of anthrax toxins: synthesis, structural features, and relative activities.
Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of beta-cyclodextrin inhibited anthrax lethal toxin action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. In the present study, we evaluate a series of new beta-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of beta-cyclodextrin with alkyl spacers of various lengths were tested for the ability to inhibit cytotoxicity of lethal toxin in cells as well as to block ion conductance through PA channels reconstituted in planar bilayer lipid membranes. Most of the tested derivatives were protective against anthrax lethal toxin action at low or submicromolar concentrations. They also blocked ion conductance through PA channels at concentrations as low as 0.1 nM. The activities of the derivatives in both cell protection and channel blocking were found to depend on the length and chemical nature of the substituent groups. One of the compounds was also shown to block the edema toxin activity. It is hoped that these results will help to identify a new class of drugs for anthrax treatment, i.e., drugs that block the pathway for toxin translocation into the cytosol, the PA channel.
Karginov
Vladimir A
VA
Innovative Biologics, Inc., 10900 University Blvd., MSN 1A8, Manassas, VA 20110, USA. vak@innovbio.com
Nestorovich
Ekaterina M
EM
Yohannes
Adiamseged
A
Robinson
Tanisha M
TM
Fahmi
Nour Eddine
NE
Schmidtmann
Frank
F
Hecht
Sidney M
SM
Bezrukov
Sergey M
SM
D000818:Animals; D000881:Anthrax / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology; D001408:Bacillus anthracis / Q000276:immunology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007202:Indicators and Reagents; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009500:Neutralization Tests
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D003505:Cyclodextrins; D007202:Indicators and Reagents; C030325:anthrax toxin; D000242:Cyclic AMP