Chimeric beta-defensin analogs, including the novel 3NI analog, display salt-resistant antimicrobial activity and lack toxicity in human epithelial cell lines.
Human beta-defensins (hBDs) are crucial peptides for the innate immune response and are thus prime candidates as therapeutic agents directed against infective diseases. Based on the properties of wild-type hBD1 and hBD3 and of previously synthesized analogs (1C, 3I, and 3N), we have designed a new analog, 3NI, and investigated its potential as an antimicrobial drug. Specifically, we evaluated the antimicrobial activities of 3NI versus those of hBD1, hBD3, 1C, 3I, and 3N. Our results show that 3NI exerted greater antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis than did hBD1 and hBD3, even with elevated salt concentrations. Moreover, its antiviral activity against herpes simplex virus 1 was greater than that of hBD1 and similar to that of hBD3. Subsequently, we investigated the cytotoxic effects of all peptides in three human epithelial carcinoma cell lines: A549 from lung, CaCo-2 from colon, and Capan-1 from pancreas. None of the analogs significantly reduced cell viability versus wild-type hBD1 and hBD3. They did not induce genotoxicity or cause an increase in the number of apoptotic cells. Using confocal microscopy, we also investigated the localization of the peptides during their incubation with epithelial cells and found that they were distributed on the cell surface, from which they were internalized. Finally, we show that hBD1 and hBD3 are characterized by high resistance to serum degradation. In conclusion, the new analog 3NI seems to be a promising anti-infective agent, particularly given its high salt resistance--a feature that is relevant in diseases such as cystic fibrosis.
CEINGE-Biotecnologie Avanzate Scarl, Naples, Italy.
Olga
O
Scudiero
Stefania
S
Galdiero
Ersilia
E
Nigro
Luigi
L
Del Vecchio
Rosa
R
Di Noto
Marco
M
Cantisani
Irene
I
Colavita
Massimiliano
M
Galdiero
Jean-Jacques
JJ
Cassiman
Aurora
A
Daniele
Carlo
C
Pedone
Francesco
F
Salvatore
D000890:Anti-Infective Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012492:Salts / Q000494:pharmacology; D023083:beta-Defensins / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology
D000890:Anti-Infective Agents; D012492:Salts; D023083:beta-Defensins