Inhibitors of human plasmin derived from the kunitz domains

Abstract

This invention provides: novel proteins, which are homologous to the first Kunitz domain (K1) of lipoprotein-associated coagulation inhibitor (LACI), and which are capable of inhibiting plasmin; uses of such novel proteins in therapeutic, diagnostic, and clinical methods; and polynucleotides that encode such novel proteins.

1 .- 11 . (canceled) 
     
     
         12 . A method of treating liver cirrhosis or amyloidosis, comprising:
 administering to a subject an effective amount of a polypeptide comprising a non-naturally occurring Kunitz domain that has the formula:   
       
         
           
                 
                 
               
                         Met-His-Ser-Phe-Cys-Ala-Phe-Lys-Ala-Xaa10-Xaa11-Gly-Xaa13-Cys-Xaa15-Xaa16- 
                     
                 
                     
                 
                   Xaa17-Xaa18-Xaa19-Arg-Trp-Xaa22-Xaa23-Asn-Ile-Phe-Thr-Arg-Gln-Cys-Xaa31-Xaa32-Phe- 
                 
                     
                 
                   Xaa34-Xaa35-Gly-Gly-Cys-Xaa39-Xaa40-Asn-Gln-Xaa43-Arg-Xaa45-Glu-Ser-Leu-Glu-Glu- 
                 
                     
                 
                   Cys-LysLys Met-Cys-Thr-Arg-Asp, 
                 
             
                
                
                
                
                
                
                
               
            
           
         
         wherein Xaa10 is selected from the group consisting of Asp, Glu, and Tyr; 
         Xaa11 is selected from the group consisting of Thr, Ala, Ser, Val, and Asp; 
         Xaa13 is selected from the group consisting of Pro, Leu, and Ala; 
         Xaa15 is selected from the group consisting of Arg and Lys; 
         Xaa16 is selected from the group consisting of Ala and Gly; 
         Xaa17 is selected from the group consisting of Arg, Lys, and Ser; 
         Xaa18 is selected from the group consisting of Phe and Ile; 
         Xaa19 is selected from the group consisting of Glu, Asp, Pro, Gly, Ser, and Ile; 
         Xaa22 is selected from the group consisting of Tyr and Phe; 
         Xaa23 is selected from the group consisting of Tyr and Phe; 
         Xaa31 is selected from the group consisting of Asp, Glu, Thr, Val, Gln, and Ala; 
         Xaa32 is selected from the group consisting of Thr, Ala, Glu, Pro, and Gln; 
         Xaa34 is selected from the group consisting of Val, Ile, Thr, Leu, Phe, Tyr, His, Asp, Ala, and Ser; 
         Xaa35 is selected from the group consisting of Tyr and Trp; 
         Xaa39 is selected from the group consisting of Glu, Gly, Asp, Arg, Ala, Gln, Leu, Lys, and Met; 
         Xaa40 is selected from the group consisting of Gly and Ala; 
         Xaa43 is selected from the group consisting of Asn and Gly; and 
         Xaa45 is selected from the group consisting of Phe and Tyr.