Indolicidin analogs with broad-spectrum antimicrobial activity and low hemolytic activity.

To create a broad-spectrum peptide biocide, we synthesized 45 analogs of antimicrobial peptide indolicidin (H-Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH2). Among them the peptides H-Ile-Leu-Pro-(2-Me)Phe-Lys-(2-Me)Phe-Pro-(2-Me)Phe-(2-Me)Phe-Pro-(2-Me)Phe-Arg-Arg-NH2 and HN2-(CH2)10-Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH2 have the broadest spectrum of antimicrobial activity and the lowest hemolytic activity. They are active against all 11 tested strains of Gram-positive bacteria, Gram-negative bacteria and fungi with MIC50 from 0.9 to 6.1 µg/ml (0.5 to 3.2 µM), being up to 3 times more active than indolicidin, and are at least 1.8 times less hemolytically active than indolicidin (reached the detection limit). These peptides are patented and could be used for further drug development as antimicrobials.

[Structure-function relationship between analogues of the antibacterial peptide indolicidin. I. Synthesis and biological activity of analogues with increased amphipathicity and elevated net positive charge of the molecule]. / Vzaimosviaz' struktura-aktivnost' v riadu analogov antibakterial'nogo peptida indolitsidina. I. Sintez i biologicheskaia aktivnost' analogov s uvelichennoi amfipatichnost'iu i povyshennym obshchim polozhitel'nym zariadom molekuly.

The antibacterial peptide indolicidin and a number of its analogues were obtained by solid phase synthesis. An optimized method of the synthesis using the Boc strategy was suggested. It was shown that the therapeutic index of indolicidin analogues increased with a decrease in the total positive charge of the molecule and its amphipathicity; i.e., the hemolytic activity of analogues within the range of concentrations examined was practically absent, while the antibacterial activity was preserved. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.