IDENTIFICATION OF INHIBITORS OF MELITTIN USING NONSUPPORT-BOUND COMBINATORIAL LIBRARIES

A strategy has been developed for the identification of inhibitors of toxins or regulatory proteins. This approach is based on blocking the access of such proteins to their biological targets during their solut ion transport. This approach uses the strength of nonsupport-bound syn thetic combinatorial libraries (SCLs) for the study of acceptor-ligand interactions. A non-receptor assisted toxin, melittin, was selected f or the present study to illustrate this application of the SCL approac h. Hexapeptide SCLs were assayed for their ability to inhibit the cyto lytic activity of melittin toward bacterial and erythrocyte cells. Ove r 20 inhibitory hexapeptides were identified following the screening a nd deconvolution processes from millions of sequences. The identified inhibitory peptides appeared to interact directly with melittin. These interactions appear to decrease melittin's ability to undergo lipid- and/or polysaccharide-induced conformational changes, and are demonstr ated by fluorescence and circular dichroism spectroscopy.