Compositions and methods for treatment of fungal infections
Novel 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 novel 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 is a first amino acid, AA2 is a second amino acid, 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 first hydrophobic amino acid, AA11 is serine or a second hydrophobic amino acid, AA6 is arginine, AA7 is arginine, AA8 is arginine, AA9 is a third amino acid, AA13 is a fourth amino acid, AA14 is a fifth amino acid, wherein the cyclic peptide comprises five arginine residues that provide a positively charged content of at least about 36% at physiological pH, and wherein the cyclic peptide is not MTD1280 (SEQ ID NO: 6).
2. The cyclic peptide of claim 1 , wherein each of the first hydrophobic amino acid and the second hydrophobic amino acid is selected from the group consisting of leucine and isoleucine.
3. The cyclic peptide of claim 1 , wherein the first amino acid is glycine.
4. The cyclic peptide of claim 1 , wherein the second amino acid is a third hydrophobic amino acid.
5. The cyclic peptide of claim 1 , wherein AA9 is a fourth hydrophobic amino acid.
6. The cyclic peptide of claim 1 , wherein at least one of the fourth and fifth amino acids is arginine.
7. The cyclic peptide of claim 1 , wherein at least one of AA4 and AA11 is not alanine.
8. A pharmaceutical formulation, comprising:
the cyclic peptide of claim 1 ; and
a pharmaceutical carrier suitable for oral administration.
9. The pharmaceutical formulation of claim 8 , wherein the pharmaceutical formulation is in dry or lyophilized form.
10. The pharmaceutical formulation of claim 8 , wherein the pharmaceutical formulation is provided as a tablet, capsule, or pill.
11. The pharmaceutical formulation of claim 10 , comprising an enteric coating.
12. The pharmaceutical formulation of claim 8 , wherein the pharmaceutical formulation is provided in a liquid form.
13. The pharmaceutical formulation of claim 12 , wherein the liquid form is encapsulated.
14. A pharmaceutical formulation comprising the cyclic peptide of claim 1 , wherein the pharmaceutical formulation is formulated for injection.