Synthesis and Antimicrobial Activity of a New Drug Based on a Retro-Analog of Cathelicidin—Polypeptide SE-33

Abstract

Polypeptide SE-33 (SETRPVLNRLFDKIRQVIRKFEKGIKEKSKRFF), which is a retro analog of natural antimicrobial protein cathelicidin LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES), was synthesized by the method of solid-phase peptide synthesis. Similar to the natural peptide, polypeptide SE-33 forms an amphipathic alpha helix but has an inverted amino acid sequence compared to cathelicidin. It has been shown the physicochemical properties of polypeptide SE-33 are similar to those of the natural compound. In vitro experiments have shown that polypeptide SE-33 exerts a bactericidal effect on the cells of Staphylococcus aureus Wood 46, which is comparable with the effect of cathelicidin LL-37, as well as pronounced antifungal activity against the clinical isolates of Candida albicans, Cryptococcus neoformans, Rhodotorula mucilaginosa, Trichosporon cutaneum, Geotrichum sp. The MICs of polypeptide SE-33 for different fungal strains were in the range of 31.2 to 1024 μg/mL. Polypeptide SE-33 demonstrated high activity in vivo in the model of vulvovaginal candidiasis (VVC) in mice comparable with that of pimafucin. In the absence of side effects and signs of pathology, polypeptide SE-33 in all doses tested (1, 10 and 50 mg/mL) statistically reduced the vaginal load of the mice compared to the placebo group. The pronounced antibacterial and antifungal activity of polypeptide SE-33, as well as the absence of a toxic effect in the VVC model in mice, suggest polypeptide SE-33 as a promising antimicrobial agent.