TY - JOUR
T1 - Inhibition of S. aureus α-hemolysin and B. anthracis lethal toxin by β-cyclodextrin derivatives
AU - Karginov, Vladimir A.
AU - Nestorovich, Ekaterina M.
AU - Schmidtmann, Frank
AU - Robinson, Tanisha M.
AU - Yohannes, Adiamseged
AU - Fahmi, Nour Eddine
AU - Bezrukov, Sergey M.
AU - Hecht, Sidney M.
N1 - Funding Information:
This work was supported by Grant 2R44AI052894-02 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health and by Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development. The authors thank Dr. M. Peredelchuk for his assistance in the optimization of the rabbit erythrocytes hemolysis assay.
PY - 2007/8/15
Y1 - 2007/8/15
N2 - Many pathogens utilize the formation of transmembrane pores in target cells in the process of infection. A great number of pore-forming proteins, both bacterial and viral, are considered to be important virulence factors, which makes them attractive targets for the discovery of new therapeutic agents. Our research is based on the idea that compounds designed to block the pores can inhibit the action of virulence factors, and that the chances to find high affinity blocking agents increase if they have the same symmetry as the target pore. Recently, we demonstrated that derivatives of β-cyclodextrin inhibited anthrax lethal toxin (LeTx) action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. To test the broader applicability of this approach, we sought β-cyclodextrin derivatives capable of inhibiting the activity of Staphylococcus aureus α-hemolysin (α-HL), which is regarded as a major virulence factor playing an important role in staphylococcal infection. We identified several amino acid derivatives of β-cyclodextrin that inhibited the activity of α-HL and LeTx in cell-based assays at low micromolar concentrations. One of the compounds was tested for the ability to block ion conductance through the pores formed by α-HL and PA in artificial lipid membranes. We anticipate that this approach can serve as the basis for a structure-directed drug discovery program to find new and effective therapeutics against various pathogens that utilize pore-forming proteins as virulence factors.
AB - Many pathogens utilize the formation of transmembrane pores in target cells in the process of infection. A great number of pore-forming proteins, both bacterial and viral, are considered to be important virulence factors, which makes them attractive targets for the discovery of new therapeutic agents. Our research is based on the idea that compounds designed to block the pores can inhibit the action of virulence factors, and that the chances to find high affinity blocking agents increase if they have the same symmetry as the target pore. Recently, we demonstrated that derivatives of β-cyclodextrin inhibited anthrax lethal toxin (LeTx) action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. To test the broader applicability of this approach, we sought β-cyclodextrin derivatives capable of inhibiting the activity of Staphylococcus aureus α-hemolysin (α-HL), which is regarded as a major virulence factor playing an important role in staphylococcal infection. We identified several amino acid derivatives of β-cyclodextrin that inhibited the activity of α-HL and LeTx in cell-based assays at low micromolar concentrations. One of the compounds was tested for the ability to block ion conductance through the pores formed by α-HL and PA in artificial lipid membranes. We anticipate that this approach can serve as the basis for a structure-directed drug discovery program to find new and effective therapeutics against various pathogens that utilize pore-forming proteins as virulence factors.
KW - Anthrax toxin
KW - Inhibitors
KW - Staphylococcus aureus
KW - α-Hemolysin
KW - β-Cyclodextrin derivatives
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U2 - 10.1016/j.bmc.2007.05.058
DO - 10.1016/j.bmc.2007.05.058
M3 - Article
C2 - 17572091
AN - SCOPUS:34250745336
SN - 0968-0896
VL - 15
SP - 5424
EP - 5431
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 16
ER -