Exendin-4 analogue pegylated with polyethylene glycol or derivative thereof, preparation method thereof, and pharmaceutical compostion for preventing or treating diabetes, containing same as active ingredient

Abstract

The present disclosure relates to an exendin-4 analogue PEGylated with polyethylene glycol or a derivative thereof, a preparation method, and a pharmaceutical composition for prevention or treatment of diabetes containing the same as an active ingredient. According to the present invention, the yield of an exendin-4 analogue can be increased via the selective PEGylation by using exendin-4 in which a cysteine is introduced into #40 site of the C-terminal, and treatment effect of medications can be increased, so that the exendin-4 analogue can be usefully applied as a composition for prevention or treatment of diseases caused by insulin hypersecretion.

We claim: 
     
         1 . An exendin-4 analogue wherein a cysteine (Cys) is introduced into #40 site of the C-terminal and is PEGylated with polyethylene glycol (PEG) or a derivative thereof. 
     
     
         2 . The exendin-4 analogue as set forth in  claim 1 , wherein, the polyethylene glycol or the derivative thereof is a linear type or a branched type. 
     
     
         3 . The exendin-4 analogue as set forth in  claim 1 , wherein, the polyethylene glycol or the derivative thereof is a dimeric type or a trimeric type. 
     
     
         4 . The exendin-4 analogue as set forth in  claim 3 , wherein, the polyethylene glycol or the derivative thereof is the trimeric type. 
     
     
         5 . The exendin-4 analogue as set forth in  claim 1 , wherein, the polyethylene glycol or the derivative thereof has a molecular weight of 5-60 kDa. 
     
     
         6 . The exendin-4 analogue as set forth in  claim 5 , wherein, the polyethylene glycol or the derivative thereof has a molecular weight of 20-50 kDa. 
     
     
         7 . The exendin-4 analogue as set forth in  claim 1 , wherein, the polyethylene glycol derivative is methoxypolyethylene glycol succinimidylpropionate, methoxypolyethylene glycol N-hydroxysuccinimide, methoxypolyethylene glycol propionaldehyde, methoxypolyethylene glycol maleimide, or multiple branched types of the derivatives. 
     
     
         8 . The exendin-4 analogue as set forth in  claim 7 , wherein, the polyethylene glycol derivative is selected from the group consisting of linear methoxypolyethylene glycol maleimide, dimeric methoxypolyethylene glycol maleimide or trimeric methoxypolyethylene glycol maleimide. 
     
     
         9 . The exendin-4 analogue as set forth in  claim 8 , wherein, the polyethylene glycol derivative is trimeric methoxypolyethylene glycol maleimide. 
     
     
         10 . A method of preparing the exendin-4 analogue as set forth in  claim 1 , the method comprising: dissolving exendin-4 in which a cysteine is introduced into #40 site of the C-terminal, and polyethylene glycol or a derivative thereof in a phosphate buffer saline solution; and reacting the dissolved ingredients at room temperature. 
     
     
         11 . The method as set forth in  claim 10 , wherein, the phosphate buffer saline has a pH range of 7.2-7.8. 
     
     
         12 . The method as set forth in  claim 10 , wherein, the reaction mole ratio of the exendin-4 having the introduced cysteine and the polyethylene glycol or the derivative thereof is 1:1-3. 
     
     
         13 . A pharmaceutical composition for prevention or treatment of diseases caused by insulin hypersecretion, containing an exendin-4 analogue as set forth in  claim 1  as an active ingredient. 
     
     
         14 . The pharmaceutical composition as set forth in  claim 13 , wherein, the diseases caused by insulin hypersecretion are Type 1 diabetes, Type 2 diabetes or diabetes complications.