The Penicillium chrysogenum-derived antifungal peptide shows no toxic effects on mammalian cells in the intended therapeutic concentration.
Certain filamentous fungi, such as the penicillin-producing strain Penicillium chrysogenum, secrete small, highly basic and cysteine-rich proteins with antifungal effects. Affected fungi include a number of important zoopathogens, including those infecting humans. Recent studies, however, have pointed to a membrane-perturbing effect of these antifungal compounds, apparent as a potassium efflux from affected fungal cells. If present on mammalian cells, this would severely hinder the potential therapeutic use of these molecules. Here we studied the effects of the P. chrysogenum-derived antifungal peptide (PAF) on a number of mammalian cells to establish whether the protein has any cytotoxic effects, alters transmembrane currents on excitable cells or activates the immune system. PAF, in a concentration range of 2-100 mug/ml, did not cause any cytotoxicity on human endothelial cells from the umbilical vein. Applied at 10 mug/ml, it also failed to modify voltage-gated potassium channels of neurones, skeletal muscle fibers, and astrocytes. PAF also left the hyperpolarization-activated non-specific cationic current (I(h)) and the L-type calcium current unaffected. Finally, up to 2 mug/ml, PAF did not induce the production of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-alpha. These results suggest that PAF should have only minor, if any, effects on mammalian cells in the intended therapeutic concentration range.
Szappanos
Henrietta
H
Department of Physiology, RCMM, MHSC, University of Debrecen, P.O. Box 22, Debrecen, Hungary.
Szigeti
Gyula Péter
GP
Pál
Balázs
B
Rusznák
Zoltán
Z
Szucs
Géza
G
Rajnavölgyi
Eva
E
Balla
József
J
Balla
György
G
Nagy
Emoke
E
Leiter
Eva
E
Pócsi
István
I
Marx
Florentine
F
Csernoch
László
L
D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D019055:No-Observed-Adverse-Effect Level; D010408:Penicillium chrysogenum; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000935:Antifungal Agents; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D011188:Potassium