Theta defensin analogs and methods of use

Abstract

Uses of novel peptide analogs of a θ-defensin that have been developed which provide a biphasic effect in treating infection and/or sepsis are described. These analogs are active at concentrations below those needed to provide a bactericidal or bacteriostatic effect, and function by initially recruiting effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response characteristic of sepsis and septic shock. 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-defensin.

What is claimed is: 
     
         1 . A method of treating a condition resulting from infectious disease or dysregulation of an immune or inflammatory response in an individual, comprising:
 identifying that the individual is in need of treatment for the infections disease or the condition resulting from dysregulation of an immune or inflammatory response; and   administering a cyclic peptide to the individual wherein the cyclic peptide has the following structure:   
       
         
           
           
               
               
           
         
         wherein AA3 and AA12 are cysteines joined by a disulfide bond, AA5 and AA10 are cysteines joined by a disulfide bond, AA4 is a first hydrophobic amino acid, AA11 is a second hydrophobic acid, AA6 is arginine, AA7 is arginine, AA8 is arginine, wherein AA1, AA2, AA9, AA13 and AA14 are amino acids, and wherein the cyclic peptide has four arginine residues that provide a positively charged content of about 28% at physiological pH. 
       
     
     
         2 . The method of  claim 1 , wherein the first hydrophobic amino acid and the second hydrophobic amino acid are leucine or isoleucine. 
     
     
         3 . The method of  claim 1 , wherein AA1 is glycine. 
     
     
         4 . The method of  claim 1 , wherein AA2 is a third hydrophobic amino acid. 
     
     
         5 . The method of  claim 1 , wherein AA9 is a fourth hydrophobic amino acid. 
     
     
         6 . The method of  claim 1 , wherein AA13 is glycine. 
     
     
         7 . The method of  claim 1 , wherein AA14 is arginine. 
     
     
         8 . The method of  claim 1 , wherein at least one of AA4 and AA11 is not alanine or serine. 
     
     
         9 . The method of  claim 1 , wherein the cyclic peptide is MTD12813 (SEQ ID NO. 2). 
     
     
         10 . The method of  claim 1 , wherein the method provides a biphasic response on administration to an organism, wherein the biphasic response comprises a phase of moderation of host inflammatory response. 
     
     
         11 . The method of  claim 1 , wherein the method inhibits TACE activity. 
     
     
         12 . The method of  claim 1 , wherein the method suppresses at least one of expression, processing, and release of a proinflammatory cytokine. 
     
     
         13 . The method 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. 
     
     
         14 . The method of  claim 1 , wherein the cyclic peptide is non-immunogenic at doses effective to treat the condition resulting the infectious disease or dysregulation of an immune or inflammatory response. 
     
     
         15 . The method of  claim 1 , wherein the condition results from dysregulation of an immune or inflammatory response is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, and sepsis. 
     
     
         16 . The method of  claim 1 , wherein the condition results from the infectious disease, wherein the infections disease results from one of the group consisting of a viral pathogen and a bacterial pathogen. 
     
     
         17 . The method of  claim 1 , wherein the cyclic peptide is administered in combination with pharmaceutical agent selected from the group consisting of an anti-viral drug, an anti-bacterial drug, an anti-fungal drug, an anti-inflammatory drug, a vasopressor, and a biologic. 
     
     
         18 . The method of  claim 17 , wherein the cyclic peptide and the pharmaceutical agent in combination provide a synergistic effect that exceeds the additive effects of the cyclic peptide and the pharmaceutical agent when administered individually.