Design and Synthesis of Melanocortin Peptides with Candidacidal and Anti-TNF-α Properties

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (5), p.1384-1388
• Main Authors: Grieco, Paolo, Rossi, Claudia, Gatti, Stefano, Colombo, Gualtiero, Carlin, Andrea, Novellino, Ettore, Lama, Teresa, Lipton, James M, Catania, Anna
• Format: Article
• Language: English
• Subjects: alpha-MSH - chemistry; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Candida albicans; Candida albicans - drug effects; Candida albicans - isolation & purification; Medical sciences; Melanocyte-Stimulating Hormones - chemical synthesis; Melanocyte-Stimulating Hormones - chemistry; Melanocyte-Stimulating Hormones - pharmacology; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040890j

α-Melanocyte stimulating hormone (α-MSH) is an endogenous antiinflammatory peptide with antimicrobial properties. We recently found that a synthetic analogue, [dNal(2‘)-7, Phe-12]-α-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-α potential of [dNal(2‘)-7, Phe-12]-α-MSH (6−13) and explored effects of amino acid deletions and substitutions on both anti-Candida and anti-TNF-α activities. The results show that anti-TNF-α 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]-α-MSH (6−13), had enhanced anti-TNF-α 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.