Method for synthesizing conformationally constrained peptides, peptidomimetics and the use thereof as synthetic vaccines

Abstract

The present invention relates to methods for synthesizing conformationally constrained peptides and cyclic peptidomimetics obtainable by these methods which are conformationally constrained due an internal cross-link. This cross-link is formed between the side chain of an amino acid residue or analog and a (2S, 4S)4-functionalized proline residue. The invention further relates to the use of (2S, 4S)-4-functionalized proline residues as building units in the synthesis of such peptidomimetics and to the use thereof as antigens, alone or in combination with suitable immunopotentiating delivery systems, for example immunopotentiating reconstituted influenza virosomes to elicit an immune response in a mammal. Moreover, the invention also relates to pharmaceutical compositions containing the same.

1 . A malaria vaccine comprising:
 a peptide comprising one or more units of formula (II):   
       
         
           
           
               
               
           
         
       
       wherein Apro is (2S,4S)-4-aminoproline; and
 one or more pharmaceutically acceptable adjuvants. 
 
     
     
         2 . The malaria vaccine of  claim 1 , wherein the peptide comprises the formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The malaria vaccine of  claim 1 , wherein the peptide is coupled to a phospholipid. 
     
     
         4 . The malaria vaccine of  claim 3 , wherein the N-terminus of the peptide is coupled via a linker to a phosphatidylethanolamine. 
     
     
         5 . The malaria vaccine of  claim 4 , wherein the linker is a dicarboxylate linker. 
     
     
         6 . The malaria vaccine of  claim 5 , wherein the dicarboxylate linker is a succinate linker. 
     
     
         7 . The malaria vaccine of  claim 4 , wherein the phosphatidylethanolamine is 1-palmityl-3-oleoylphosphatidylethanolamine (PE). 
     
     
         8 . The malaria vaccine of  claim 1 , wherein the peptide is combined with an immunopotentiating delivery system selected from the group consisting of liposomes, multiple-antigen peptides, and immunopotentiating reconstituted virosomes. 
     
     
         9 . The malaria vaccine of  claim 2 , further comprising a 1-palmityl-3-oleoylphosphatidylethanolamine (PE) moiety at the N-terminus attached to an immunopotentiating reconstituted virosome. 
     
     
         10 . The malaria vaccine of  claim 1 , wherein the peptide can mimic the surface structure of a circumsporozoite (CS) protein, thereby eliciting a humoral immune response. 
     
     
         11 . The malaria vaccine of  claim 1 , wherein the peptide can elicit the production of an antibody capable of cross-reacting with a native circumsporozoite (CS) protein of a  Plasmodium.    
     
     
         12 . A method of producing a malaria vaccine comprising:
 providing a peptide comprising one or more units of formula (II):   
       
         
           
           
               
               
           
         
       
       wherein Apro is (2S,4S)-4-aminoproline and
 providing one or more pharmaceutically acceptable adjuvants. 
 
     
     
         13 . The method of  claim 12 , wherein the peptide comprises the formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 12 , wherein the peptide is coupled to a phospholipid. 
     
     
         15 . The method of  claim 14 , wherein the N-terminus of the peptide is coupled via a linker to a phosphatidylethanolamine. 
     
     
         16 . The method of  claim 15 , wherein the linker is a dicarboxylate linker. 
     
     
         17 . The method of  claim 16 , wherein the dicarboxylate linker is a succinate linker. 
     
     
         18 . The method of  claim 15 , wherein the phosphatidylethanolamine is 1-palmityl-3-oleoylphosphatidylethanolamine (PE). 
     
     
         19 . The method of  claim 12 , wherein the peptide is combined with an immunopotentiating delivery system selected from the group consisting of liposomes, multiple-antigen peptides, and immunopotentiating reconstituted virosomes. 
     
     
         20 . The method of  claim 13 , further comprising a 1-palmityl-3-oleoylphosphatidylethanolamine (PE) moiety at the N-terminus attached to an immunopotentiating reconstituted virosome. 
     
     
         21 . The method of  claim 12 , wherein the peptide can mimic the surface structure of a circumsporozoite (CS) protein, thereby eliciting a humoral immune response. 
     
     
         22 . The method of  claim 12 , wherein the peptide can elicit the production of an antibody capable of cross-reacting with a native circumsporozoite (CS) protein of a  Plasmodium.