Degradable clostridial toxins
The specification discloses modified Clostridial toxins comprising a PAR ligand domain, a Clostridial toxin enzymatic domain, a Clostridial toxin translocation domain and a Clostridial toxin binding domain; polynucleotide molecules encoding modified Clostridial toxins comprising a PAR ligand domain, a Clostridial toxin enzymatic domain, a Clostridial toxin translocation domain and a Clostridial toxin binding domain; and method of producing modified Clostridial toxins comprising a PAR ligand domain, a Clostridial toxin enzymatic domain, a Clostridial toxin translocation domain and a Clostridial toxin binding domain.
1. A modified Clostridial toxin comprising:
a) a protease-activated G protein-coupled receptor (PAR) ligand domain;
b) a Clostridial toxin enzymatic domain;
c) a Clostridial toxin translocation domain; and
d) a non-Clostridial toxin binding domain, wherein the non-Clostridial binding domain binds to a target cell surface receptor system other than the one used by a Clostridial binding domain and allows subsequent passage of the modified Clostridial toxin into an endosome within the target cell;
wherein the non-Clostridial toxin binding domain is selected from the group consisting of a Bradykinin, a Dynorphin, a β-endorphin, an Etorphine, an Endomorphin-1, an Endomorphin-2, a Leu-enkephalin, a Met-enkephalin, a Galanin, a Lofentanil or a Nociceptin.
2. A modified Clostridial toxin comprising:
a) a protease-activated G protein-coupled receptor (PAR) ligand domain;
b) a Clostridial toxin enzymatic domain;
c) a Clostridial toxin translocation domain; and
d) a non-Clostridial toxin binding domain, wherein the non-Clostridial binding domain binds to a target cell surface receptor system other than the one used by a Clostridial binding domain and allows subsequent passage of the modified Clostridial toxin into an endosome within the target cell;
wherein the non-Clostridial toxin binding domain is a Nociceptin.