Identification of peptides that neutralize bacterial endotoxins using beta-hairpin conformationally restricted libraries.
Bacterial endotoxins are the major mediator of septic shock; therefore, endotoxin-neutralizing molecules could have biomedical applications. The septic shock cascade relies in a series of molecular recognition processes. The large contact-surface described for the interacting macromolecules, in most cases, prevents the identification of small molecules that could modulate such recognition events. Here we report on a beta-hairpin conformationally restricted combinatorial library that has been generated and screened towards the identification of new peptides that neutralize bacterial endotoxins. Starting with a de novo designed linear peptide that shows a beta-hairpin structure population of around 30%, (Ramirez-Alvarado, M., Blanco, F. J. and Serrano, L. Nat. Struc. Biol., 7, 604-612 (1996)), we selected four positions to build up a combinatorial library of 20(4) sequences. Deconvolution of the library reduced such a sequence complexity to 8 defined sequences. The newly identified peptides have a biological activity equivalent to that reported for peptides derived from natural endotoxin-binding proteins.
Dept. Bioquímica i Biologia Molecular, Universitat de València, E-46100 Burjassot, València, Spain.
H
H
González-Navarro
P
P
Mora
M
M
Pastor
L
L
Serrano
I
I
Mingarro
E
E
Pérez-Payá
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D002942:Circular Dichroism; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004731:Endotoxins / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence
D001426:Bacterial Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D019151:Peptide Library; D010455:Peptides