Design and synthesis of melanocortin peptides with candidacidal and anti-TNF-α properties

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.