Protegrins

Abstract

Peptide-based compounds containing four invariant cysteine residues which have been optionally oxidized to contain two intramolecular disulfide bonds, or modified forms where the cysteines are replaced are useful as preservatives and in preventing, treating, or ameliorating viral or microbial infection in animals and plants, and in inactivating endotoxin. These compounds, in one embodiment, are of the formula: A 1 -A 2 -A 3 -A 4 -A 5 -C 6 -A 7 -C 8 -A 9 -A 10 -A 11 -A 12 -C 13 -A 14 -C 15 -A 16 -(A 17 -(A 18 )   (1) and the N-terminal acylated and/or C-terminal amidated or esterified forms thereof, which is either in the optionally —SH stablizied linear or in a cystine-bridged form wherein each of A 1 and A 9 is independently a basic amino acid; each of A 2 and A 3 is independently a small amino acid; each of A 5 , A 7 , A 12 , A 14 and A 16 is independently a hydrophobic amino acid; A 4 is a basic or a small amino acid; A 10 is a basic or a small amino acid or is proline; A 11 is a basic or hydrophobic amino acid; A 17 is not present or, if present, is a small amino acid; A 18 is not present or, if present, is a basic amino acid; or a modified form of formula (1) and the N-terminal acylated and/or C-terminal amidated or esterified forms thereof wherein each of 1-4 cysteines is independently replaced by a hydrophobic amino acid or a small amino acid.

What is claimed is:  
     
         1 . A purified and isolated or recombinantly produced compound having the formula:  
       A 1 -A 2 -A 3 -A 4 -A 5 -C 6 -A 7 -C 8 -A 9 -A 10 -A 11 -A 12 -C 13 -A 14 -C 15 -A 16 -A 17 -A 18    (1)  or a pharmaceutically acceptable salt or an N-terminal acylated or C-terminal amidated or esterified form thereof, which is either in a linear form or in a cystine-bridged form, wherein: 
 each of A 1  and A 9  is independently a basic amino acid;  
 each of A 2  and A 3  is independently a small amino acid;  
 each of A 5 , A 7 , A 12 , A 14  and A 16  is independently a hydrophobic amino acid;  
 A 4  is a basic or a small amino acid;  
 A 10  is a basic or a small amino acid or is proline;  
 A 11  is a basic or a hydrophobic amino acid;  
 A 17  is not present or, if present, is a small amino acid;  
 A 18  is not present or, if present, is a basic amino acid; and  
 each of C 6 , C 8 , C 13  and C 15  is independently selected from the group consisting of cysteine, a hydrophobic amino acid, a large polar amino acid and a small amino acid.  
   
     
     
         2 . The compound of  claim 1  which has one or more characteristics selected from the group consisting of: 
 the C-terminal carboxyl is of the formula selected from the group consisting of COOH or salts thereof; COOR, CONH 2 , CONHR and CONR 2  wherein each R is independently a hydrocarbyl (1-6C);  
 the amino group at the N-terminus is of the formula NH 2  or NHCOR wherein R is a hydrocarbyl (1-6C);  
 each of A 1  and A 9  is independently selected from the group consisting of R, K and Har;  
 each of A 2  and A 3  is independently selected from the group consisting of G, A, S and T;  
 A 4  is R or G;  
 each of A 5 , A 14 , and A 16  is independently selected from the group consisting of I, V, NLe, L and F;  
 each of A 7  and A 12  is independently selected from the group consisting of I, V, L, W, Y and F;  
 A 10  is R, G or P; and  
 A 11  is R or W.  
 
     
     
         3 . The compound of  claim 1  which has antimicrobial or antiviral activity against pathogens associated with sexually transmitted disease.  
     
     
         4 . The compound of  claim 1  which has antimicrobial or antiviral activity against  Escherichia coli, Listeria monocytogenes, Candida albicans, Pseudomonas aeruginosa, Kiebsiella pneumoniae, Salmonella typhimurium, Staphylococcus aureus, Histoplasma capsulatum, Myobacterium aviumintracellulare, Mycobacterium tuberculosis, Vibrio vulnificus, Chlamydia trachomatis, Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis,  Herpes simplex virus type 1, Herpes simplex virus type 2, human immunodeficiency virus,  Hemophilus ducreyi,  or human papilloma virus.  
     
     
         5 . The compound of  claim 1  which is selected from the group consisting of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   PG-1: 
                   RGGRLCYCRRRFCVCVGR; 
                   (SEQ ID NO:16) 
                 
                     
                     
                 
                     
                   PG-2: 
                   RGGRLCYCRRRFCICV; 
                   (SEQ ID NO:17) 
                 
                     
                     
                 
                     
                   PG-3: 
                   RGGGLCYCRRRFCVCVGR; 
                   (SEQ ID NO:18) 
                 
                     
                     
                 
                     
                   PG-4: 
                   RGGRLCYCRGWICFCVGR; 
                   (SEQ ID NO:19) 
                 
                     
                     
                 
                     
                   PG-5: 
                   RGGRLCYCRPRFCVCVGR; 
                   (SEQ ID NO:20) 
                 
                     
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and the amidated forms thereof either in linear or cystine-bridged form.  
       
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         7 . A method of inhibiting the growth of a microbe or the replication of a virus which comprises the step of contacting said virus or said microbe with an amount of a compound according to  claim 1  effective to inhibit said growth or said replication.  
     
     
         8 . The method of  claim 7  in which the microbe is a bacteria.  
     
     
         9 . The method of  claim 7  in which the microbe or virus is a sexually-transmitted microbe or virus.  
     
     
         10 . The method of  claim 9  in which the sexually-transmitted microbe or virus is selected from the group consisting of HIV-1,  Chlamydia trachomatis, Treponema pallidum, Neisseria gonorrhoeae, Trichonomis vaginalis,  HSV-1, HSV-2,  Hemophilus ducreyi  and human papilloma virus  
     
     
         11 . The method of  claim 7  in which the microbe or virus is HIV.  
     
     
         12 . The method of  claim 7  in which the microbe or virus is methicillin-resistant  S. aureus  (MRSA) or vancomycin-resistant  E. faecalis  (VREF).  
     
     
         13 . A method to treat or prevent a microbial or viral infection in a subject, which method comprises administering to a subject in need of such treatment an amount of a compound according to  claim 1  effective to ameliorate or prevent said infection in the subject.  
     
     
         14 . The method of  claim 13  in which the infection is a bacterial infection.  
     
     
         15 . The method of  claim 14  in which the bacteria is selected from the group consisting of  E. Coli, L. monocytogenes, B. subtilis, S. typhimurium, S. aureus  and  P. aeruginosa.    
     
     
         16 . The method of  claim 13  in which the infection is caused by a sexually-transmitted pathogen.  
     
     
         17 . The method of  claim 16  in which the sexually-transmitted pathogen is selected from the group consisting of HIV-1,  Chlamydia trachomatis, Treponema pallidum, Neisseria gonorrhoeae, Trichonomis vaginalis,  HSV-1, HSV-2,  Hemophilus ducreyi  and human papilloma virus.  
     
     
         18 . The method of  claim 13  in which the infection is an HIV infection.  
     
     
         19 . The method of  claim 13  in which the infection is a methicillin-resistant  S. aureus  (MRSA) or vancomycin-resistant  E. faecalis  (VREF) infection.  
     
     
         20 . The method of  claim 13  in which the compound is administered topically.  
     
     
         21 . The method of  claim 13  in which the compound is administered prophylactically.