Peptide inhibitors of phosphoglycerate mutase and methods of use

Abstract

Disclosed herein are isolated peptides inhibit activity of a cofactor-independent phosphoglycerate mutase. In some examples, the isolated peptide is 6-20 amino acids long and includes the amino acid sequence of any one of SEQ ID NOs: 1-22 or 54, an analog or derivative thereof, or a pharmaceutically acceptable salt or ester thereof. In some examples, the peptide is a cyclic peptide with an N-terminal ring of 6-15 amino acids (for example, 6-10 amino acids) and a C-terminal linear portion of 1-9 amino acids (for example, 3-8 amino acids. Also disclosed h are methods of treating or inhibiting an infection in a subject, including administering to the subject an effective amount of a composition including one of more of the disclosed peptides, or analogs or derivative thereof, or pharmaceutically acceptable salts or esters thereof.

We claim: 
     
         1 . An isolated peptide comprising the amino acid sequence of any one of SEQ ID NOs: 7-9. 
     
     
         2 . The isolated peptide of  claim 1 , wherein the N-terminal amino acid is D-N-chloroacetyl tyrosine. 
     
     
         3 . The isolated peptide of  claim 2 , wherein the peptide comprises: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 7) 
                 
                     
                     Ac-D YDYPGDYSYLYGTCG; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 8)  
                 
                     
                     Ac-D YDYPGDYSYLY; 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                     Ac-D YLYGTCG. 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . A pharmaceutical composition comprising the isolated peptide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         5 . A method of treating or inhibiting infection with an organism expressing at least one cofactor-independent phosphoglycerate mutase in a subject, comprising administering to the subject an effective amount of the isolated peptide of  claim 1 . 
     
     
         6 . The method of  claim 5 , wherein the subject is infected with an organism selected from the group consisting of a nematode, a trypanosome, a helminth, a protozoan parasite, or a bacterium. 
     
     
         7 . The method of  claim 6 , wherein the subject is infected with a nematode, and the nematode comprises one or more of  Brugia malayi, Brugia timori, Wuchereria bancrofti, Onchocerca volvulus, Loa, Mansonella streptocerca, Mansonella perstans, Mansonella ozzardi, Dirofilaria immitis, Trichinella, Parafilaria bovicola, Onchocerca dermatan, Onchocerca ochengi, Onchocerca dukei, Stenofilaria assamensis , and  Parafilaria multipapillosa.    
     
     
         8 . The method of  claim 6 , wherein the subject is infected with a bacterium and the bacterium comprises one or more of  Staphylococcus aureus, Bacillus anthracia, Streptococcus pneumoniae , and  Escherichia coli.    
     
     
         9 . The method of  claim 5 , wherein the peptide is administered to the subject orally, intravenously, or topically. 
     
     
         10 . The method of  claim 5 , further comprising administering one or more of an antiparasitic or antibiotic agent to the subject. 
     
     
         11 . An isolated cyclic peptide comprising the any one of the peptides in  FIG. 21 , SEQ ID NO: 21 or SEQ ID NO: 22. 
     
     
         12 . The isolated cyclic peptide of  claim 11 , wherein the peptide comprises: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising the isolated cyclic peptide of  claim 11  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method of treating or inhibiting infection with an organism expressing at least one cofactor-independent phosphoglycerate mutase in a subject, comprising administering to the subject an effective amount of the isolated cyclic peptide of  claim 11 . 
     
     
         15 . The method of  claim 14 , wherein the subject is infected with an organism selected from the group consisting of a nematode, a trypanosome, a helminth, a protozoan parasite, or a bacterium. 
     
     
         16 . The method of  claim 15 , wherein the subject is infected with a nematode, and the nematode comprises one or more of  Brugia malayi, Brugia timori, Wuchereria bancrofti, Onchocerca volvulus, Loa loa, Mansonella streptocerca, Mansonella perstans, Mansonella ozzardi, Dirofilaria immitis, Trichinella , Parafilaria  bovicola, Onchocerca dermatan, Onchocerca ochengi, Onchocerca dukei, Stenofilaria assamensis , and  Parafilaria multipapillosa.    
     
     
         17 . The method of  claim 15 , wherein the subject is infected with a bacterium and the bacterium comprises one or more of  Staphylococcus aureus, Bacillus anthracia, Streptococcus pneumoniae , and  Escherichia coli.    
     
     
         18 . The method of  claim 14 , wherein the cyclic peptide is administered to the subject orally, intravenously, or topically. 
     
     
         19 . The method of  claim 14 , further comprising administering one or more of an antiparasitic or antibiotic agent to the subject.