Search for cyclodextrin-based inhibitors of anthrax toxins: Synthesis, structural features, and relative activities

Vladimir A. Karginov, Ekaterina M. Nestorovich, Adiamseged Yohannes, Tanisha M. Robinson, Nour Eddine Fahmi, Frank Schmidtmann, Sidney Hecht, Sergey M. Bezrukov

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of β-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 β-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of β-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.

Original languageEnglish (US)
Pages (from-to)3740-3753
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume50
Issue number11
DOIs
StatePublished - Nov 2006
Externally publishedYes

Fingerprint

Cyclodextrins
Antigens
Ions
Anthrax
Cytoprotection
Drug Design
Lipid Bilayers
Membrane Lipids
Pharmaceutical Preparations
Cytosol
Edema
anthrax toxin

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Karginov, V. A., Nestorovich, E. M., Yohannes, A., Robinson, T. M., Fahmi, N. E., Schmidtmann, F., ... Bezrukov, S. M. (2006). Search for cyclodextrin-based inhibitors of anthrax toxins: Synthesis, structural features, and relative activities. Antimicrobial Agents and Chemotherapy, 50(11), 3740-3753. https://doi.org/10.1128/AAC.00693-06

Search for cyclodextrin-based inhibitors of anthrax toxins : Synthesis, structural features, and relative activities. / Karginov, Vladimir A.; Nestorovich, Ekaterina M.; Yohannes, Adiamseged; Robinson, Tanisha M.; Fahmi, Nour Eddine; Schmidtmann, Frank; Hecht, Sidney; Bezrukov, Sergey M.

In: Antimicrobial Agents and Chemotherapy, Vol. 50, No. 11, 11.2006, p. 3740-3753.

Research output: Contribution to journalArticle

Karginov, VA, Nestorovich, EM, Yohannes, A, Robinson, TM, Fahmi, NE, Schmidtmann, F, Hecht, S & Bezrukov, SM 2006, 'Search for cyclodextrin-based inhibitors of anthrax toxins: Synthesis, structural features, and relative activities', Antimicrobial Agents and Chemotherapy, vol. 50, no. 11, pp. 3740-3753. https://doi.org/10.1128/AAC.00693-06
Karginov, Vladimir A. ; Nestorovich, Ekaterina M. ; Yohannes, Adiamseged ; Robinson, Tanisha M. ; Fahmi, Nour Eddine ; Schmidtmann, Frank ; Hecht, Sidney ; Bezrukov, Sergey M. / Search for cyclodextrin-based inhibitors of anthrax toxins : Synthesis, structural features, and relative activities. In: Antimicrobial Agents and Chemotherapy. 2006 ; Vol. 50, No. 11. pp. 3740-3753.
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