Muteins of fibroblast growth factor 21

Abstract

The present invention relates to novel muteins of human fibroblast growth factor 21 with improved pharmaceutical properties. Both protein and the respective encoding nucleic acid species are disclosed. The invention also embodies vectors and host cells for the propagation of said nucleic acid sequences and the production of said muteins. Also disclosed are methods for treating type 2 diabetes, obesity, metabolic syndrome, and in reducing the mortality and morbidity of critically ill patients.

1 - 41 . (canceled) 
     
     
         42 . A mutein of human fibroblast growth factor 21 (FGF-21), consisting of human FGF-21 wherein a substitution of a charged and/or polar but uncharged amino acid for one or more amino acids at the positions from the group consisting of: glutamine 54, arginine 77, leucine 139, alanine 145, leucine 146, isoleucine 152, glutamine 156, glycine 161, serine 163, wherein the numbering of the amino acids is based on SEQ ID NO:1. 
     
     
         43 . The mutein of  claim 42  wherein the charged amino acid is selected from the group consisting of aspartate, glutamate, and non-naturally occurring analogs thereof. 
     
     
         44 . The mutein of  claim 42  wherein the polar but uncharged amino acid is selected from the group consisting of serine, threonine, asparagine, glutamine, and non-naturally occurring analogs thereof. 
     
     
         45 . The mutein of  claim 42 , wherein said mutein is selected from the group consisting of Leu139Glu-human FGF-21, Ala145Glu-human FGF-21, Leu146Glu-human FGF-21, Ile152Glu-human FGF-21, Gln156Glu-human FGF-21, Ser163Glu-human FGF-21, Ile152Glu-human FGF-21, Ser163Glu-human FGF-21, Arg77Glu-human FGF-21, and Gln54Glu-human FGF-21. 
     
     
         46 . A pharmaceutical composition comprising a therapeutically effective amount of a mutein of  claim 45  and a pharmaceutically acceptable carrier. 
     
     
         47 . A biologically active peptide of a mutein of human FGF-21 consisting of a human FGF-21 wherein:
 (a) a substitution of a charged and/or polar but uncharged amino acid for one or more amino acids at the positions from the group consisting of: glutamine 54, arginine 77, leucine 139, alanine 145, leucine 146, isoleucine 152, glutamine 156, glycine 161, serine 163, wherein the numbering of the amino acids is based on SEQ ID NO:1; and   (b) one, two, three, or four amino acids are truncated from the N-terminus.