B PI-DERIVED SYNTHETIC PEPTIDES - SYNERGISTIC EFFECTS IN TETHERED BACTERICIDAL AND ENDOTOXIN NEUTRALIZING PEPTIDES/

Human neutrophil bactericidal protein (B/PI) is known for its ability to kill bacteria and to neutralize the action of endotoxin. Short line ar peptides derived from residues 80-109 have been synthesized and the ir bactericidal and endotoxin neutralizing activities have been assaye d. A series of 'walk-through' decapeptides, overlapping 3 to 4 residue s, indicates that endotoxin neutralizing and partial bactericidal acti vities can be localized within the N- and C-terminal portions, respect ively, of the 80-109 sequence. Bactericidal activity toward Pseudomona s aeruginosa was localized in central peptides of the walk-through ser ies and greatest in peptide 90-99. By using longer peptides, residues 86-104 and 82-108, both bactericidal and endotoxin neutralizing activi ties are significantly enhanced. Bactericidal activity of peptide 82-1 08 is now only 6-fold less than that of parent B/PI and 9-fold more po tent than peptide 86-104. The 82-108 peptide was 7-fold more active at endotoxin neutralization than 86-104 but showed less enhanced activit y, being approx. 470-times less active than B/PI. Cyclized 82-108 pept ide retained bactericidal activity but did not improve in capacity to neutralize endotoxin.