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
beta-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
beta-cyclodextrin derivatives capable of inhibiting the activity of Staphylococcus aureus alpha-
hemolysin (alpha-HL), which is regarded as a major
virulence factor playing an important role in
staphylococcal infection. We identified several
amino acid derivatives of
beta-cyclodextrin that inhibited the activity of alpha-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 alpha-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.