Design and synthesis of melanocortin peptides with candidacidal and anti-TNF-alpha properties.
Alpha-melanocyte stimulating hormone (alpha-MSH) is an endogenous antiinflammatory peptide with antimicrobial properties. We recently found that a synthetic analogue, [dNal(2')-7, Phe-12]-alpha-MSH (6-13), was considerably more potent in killing Candida albicans, but the anti-cytokine potential of the molecule was not investigated. Because molecules that combine candidacidal and antiinflammatory properties could be very useful in clinical practice, we measured the anti-TNF-alpha potential of [dNal(2')-7, Phe-12]-alpha-MSH (6-13) and explored effects of amino acid deletions and substitutions on both anti-Candida and anti-TNF-alpha activities. The results show that anti-TNF-alpha properties of this candidacidal peptide are only marginally increased relative to the native sequence. Conversely, we found that a closely related candidacidal analogue, [dNal(2')-7, Pro-12]-alpha-MSH (6-13), had enhanced anti-TNF-alpha effects in vitro and in vivo. This peptide, and other melanocortins with a similar dual effect, could be very useful to eradicate infections and, concurrently, reduce inflammatory reactions.
Grieco
Paolo
P
Department of Pharmaceutical Chemistry and Toxicology, Università di Napoli, 80131 Naples, Italy.
Rossi
Claudia
C
Gatti
Stefano
S
Colombo
Gualtiero
G
Carlin
Andrea
A
Novellino
Ettore
E
Lama
Teresa
T
Lipton
James M
JM
Catania
Anna
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification; D009074:Melanocyte-Stimulating Hormones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000521:alpha-MSH / Q000737:chemistry*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000935:Antifungal Agents; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C472570:alpha-melanocyte stimulating hormone (6-13), Nal(7)-Phe(12)-; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones