Neurotoxins exhibiting shortened biological activity

摘要

The present invention relates to the pharmaceutical field. Specifically, it contemplates a polynucleotide encoding a Neurotoxin polypeptide exhibiting a reduced duration of biological effect in a subject, wherein the polypeptide comprises at least one degradation signal in the light chain as well as vectors and host cells comprising the polynucleotide, polypeptides encoded thereby and antibodies specifically binding to the polypeptides. Moreover, the invention relates to medicaments comprising the polynucleotides and polypeptides as well as specific therapeutic applications thereof. Furthermore, the present invention contemplates methods for the manufacture of the polypeptides and medicaments.

主权项

1. A modified neurotoxin polypeptide exhibiting a reduced duration of muscle paralysis in a subject, wherein the neurotoxin polypeptide comprises at least one degradation signal in a light chain of the neurotoxin polypeptide, wherein the degradation signal in the light chain of the neurotoxin polypeptide is selected from:
a) at least one internally or terminally introduced PEST motif; b) at least one internally or terminally introduced E3 ligase recognition motif; c) an N-terminal oligo-lysine residue; d) an N-terminally linked ubiquitin; e) a substitution of the N-terminal praline with a basic amino acid; f) substitutions of surface displayed amino acid residues with lysine; and g) a substitution of the N-terminal praline with a basic amino add in combination with substitutions of surface displayed amino add residues with lysine.