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 solution transport. This approach uses the strength of nonsupport-bound synthetic combinatorial libraries (SCLs) for the study of acceptor-ligand interactions. A non-receptor assisted toxin, melittin, was selected for the present study to illustrate this application of the SCL approach. Hexapeptide SCLs were assayed for their ability to inhibit the cytolytic activity of melittin toward bacterial and erythrocyte cells. Over 20 inhibitory hexapeptides were identified following the screening and 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 demonstrated by fluorescence and circular dichroism spectroscopy.
Blondelle
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SE
Torrey Pines Institute for Molecular Studies, San Diego, California 92121, USA.
Houghten
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RA
Pérez-Payá
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E
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002942:Circular Dichroism; D016208:Databases, Factual; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008555:Melitten / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009842:Oligopeptides; D008555:Melitten