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Journal of Antimicrobial Chemotherapy (1999) 44, 33-41
© 1999 The British Society for Antimicrobial Chemotherapy

Lentivirus-derived antimicrobial peptides: increased potency by sequence engineering and dimerization

Sarah Burroughs Tenczaa,{dagger}, Donald J. Creightona, Tao Yuanb, Hans J. Vogelb, Ronald C. Montelaroa,* and Timothy A. Mietznera

a Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; b Department of Biological Sciences, University of Calgary, Calgary, Alta., T2N 1N4, Canada

We have previously described a family of cationic amphipathic peptides derived from lentivirus envelope proteins that have properties similar to those of naturally occurring antimicrobial peptides. Here, we explored the effects of amino acid truncations and substitutions on the antimicrobial potency and selectivity of the prototype peptide, LLP1. Removal of seven residues from the C-terminus of LLP1 had little effect on potency, but abrogated haemolytic activity. Replacement of the two glutamic acid residues of LLP1 with arginine resulted in a peptide with greater bactericidal activity. We discovered that the cysteine-containing peptides spontaneously formed disulphide-linked dimers, which were 16-fold more bactericidal to Staphylococcus aureus. Monomeric and dimeric LLP1 possessed similar alpha helical contents, indicating that disulphide formation did not alter the peptide’s secondary structure. The dimerization strategy was applied to magainin 2, enhancing its bactericidal activity eight-fold. By optimizing all three properties of LLP1, a highly potent and selective peptide, named TL-1, was produced. This peptide is significantly more potent than LLP1 against Gram-positive bacteria while maintaining high activity against Gram-negative organisms and low activity against eukaryotic cells. In addition to new antimicrobial peptides, these studies contribute useful information on which further peptide engineering efforts can be based.

* Correspondence address. Room W1144 Biomedical Science Tower, Pittsburgh, PA 15261, USA. Tel: +1-412-648-8869; Fax: +1-412-383-8859; E-mail: rmont{at}pop.pitt.edu

{dagger} Present address. Cellomics Inc., 635 William Pitt Way, Pittsburgh, PA 15238, USA.


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