Designed β-sheet-forming peptide 33mers with potent human bactericidal/permeability increasing protein-like bactericidal and endotoxin neutralizing activities

Kevin H Mayo, Judith Haseman, Elena Ilyina, Beulah Gray

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Novel peptide 33mers have been designed by incorporating β-conformation stabilizing residues from the β-sheet domains of α-chemokines and functionally important residues from the β-sheet domain of human neutrophil bactericidal protein (B/PI). B/PI is known for its ability to kill bacteria and to neutralize the action of bacterial endotoxin (lipopolysaccharide, LPS) which can induce septic shock leading to eventual death. Here, the goal was to make short linear peptides which demonstrate good β-sheet folding and maintain bioactivity as in native B/PI. A library of 24 peptide 33mers (βpep-1 to βpep-24) were synthesized with various amino acid substitutions. CD and NMR data acquired in aqueous solution indicate that βpep peptides form β-sheet structure to varying degrees and self-associate as dimers and tetramers like the α-chemokines. Bactericidal activity toward Gram-negative Pseudomonas aeruginosa was tested, and βpep-19 was found to be only about 5-fold less potent (62% kill at 1.2x10-7 M) than native B/PI (80% kill at 2.9x10-8 M). At LPS neutralization, βpep-2 and -23 were found to be most active (66-78% effective at 1.2x10-6 M), being only about 50-100-fold less active than B/PI (50% at 1.5x10-8 M). In terms of structure-activity relations, β-sheet structural stability correlates with the capacity to neutralize LPS, but not with bactericidal activity. Although a net positive charge is necessary for activity, it is not sufficient for optimal activity. Hydrophobic residues tend to influence activities indirectly by affecting structural stability. Furthermore, results show that sequentially and spatially related residues from the β-sheet domain of native B/PI can be designed into short linear peptides which show good β-sheet folding and retain much of the native activity. This research contributes to the development of solutions to the problem of multiple drug-resistant, opportunistic microorganisms like P. aeruginosa and of agents effective at neutralizing bacterial endotoxin. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)81-92
Number of pages12
JournalBiochimica et Biophysica Acta - General Subjects
Issue number1
StatePublished - Sep 16 1998

Bibliographical note

Funding Information:
This work was supported by generous research grants from the Graduate School of the University of Minnesota and by the Minnesota Medical Foundation. We are grateful to Denisha Walik of the Microchemical Facility for expertise in the synthesis of peptides.

Copyright 2007 Elsevier B.V., All rights reserved.


  • Bactericidal
  • Circular dichroism
  • Endotoxin neutralizing
  • NMR
  • Peptide
  • β-Sheet


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