Compositions and methods for treatment of fungal infections
Peptide analogs of a θ-defensin have been developed that provide a biphasic effect in treating disseminated fungal disease and/or associated septic shock. These analogs are active at concentrations below those needed to provide a fungicidal effect, and function by initially mobilizing effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response. These θ-defensin analogs are protective at concentrations where naturally occurring θ-defensins have no apparent effect, and include a core set of structural and sequence features not found in native θ-defensins.
1. A cyclic peptide consisting of 14 amino acids and having the following structure:
wherein AA1, AA2, AA13, and AA14 are amino acids, AA3 and AA12 are cysteines joined by a disulfide bond, AA5 and AA10 are cysteines joined by a disulfide bond, AA4 is serine or a hydrophobic amino acid, AA9 and AA11 are a hydrophobic amino acids, two of AA6, AA7, and AA8 are arginine, wherein a β turn segment of the cyclic peptide defined by AA6, AA7, AA8, and AA9 does not include more than two adjacent arginines, and wherein the cyclic peptide comprises five or more arginine residues that provide a positively charged content of at least about 36% at physiological pH, wherein the cyclic peptide has an antifungal activity.
2. The cyclic peptide of claim 1 , wherein AA1 is glycine.
3. The cyclic peptide of claim 1 , wherein AA2 is a hydrophobic amino acid.
4. The cyclic peptide of claim 1 , wherein at least one of AA13 and AA14 is arginine.
5. The cyclic peptide of claim 1 , wherein the cyclic peptide is an analog of a θ-defensin, and wherein the cyclic peptide provides improved survival when applied systemically in a murine disseminated candidiasis model relative to the θ-defensin.
6. The cyclic peptide of claim 1 , wherein the cyclic peptide provides a biphasic response on application to a murine model of disseminated candidiasis, wherein the biphasic response comprises a first phase of mobilization of host effector cells having antifungal activity and a second phase of moderation of host inflammatory response.
7. The cyclic peptide of claim 1 , wherein the cyclic peptide comprises a tumor necrosis factor alpha converting enzyme (TACE) inhibiting activity.
8. The cyclic peptide of claim 1 , wherein the cyclic peptide suppresses at least one of expression, processing, and release of a proinflammatory cytokine.
9. The cyclic peptide of claim 1 , wherein the cyclic peptide retains activity following exposure to environmental extremes of temperature, low pH, freezing and/or thawing, and dissolution in a biological matrix.
10. The cyclic peptide of claim 1 , wherein the cyclic peptide is non-immunogenic at doses effective to treat disseminated fungal infection.
11. A cyclic peptide consisting of 14 amino acids and having the following structure:
wherein AA1 is G, AA2 is V, AA3 is C, AA4 is R, AA5 is C, AA6 is R, AA7 is R, AA8 is G, AA9 is V, AA10 is C, AA11 is R, AA12 is C, AA13 is R, and AA14 is R, wherein AA3 and AA12 are joined by a cysteine bond, and AA5 and AA10 are joined by a cysteine bond.