Non-cytotoxic protein conjugates

摘要

The present invention is directed to non-cytotoxic protein conjugates for inhibition or reduction of exocytic fusion in a nociceptive sensory afferent cell. The protein conjugates comprise: (i) a Targeting Moiety (TM), wherein the TM is an agonist of a receptor present on a nociceptive sensory afferent cell, and wherein the receptor undergoes endocytosis to be incorporated into an endosome within the nociceptive sensory afferent cell; (ii) a non-cytotoxic protease or a fragment thereof, wherein the protease or protease fragment is capable of cleaving a protein of the exocytic fusion apparatus of the nociceptive sensory afferent cell; and (iii) a Translocation Domain, wherein the Translocation Domain translocates the protease or protease fragment from within the endosome, across the endosomal membrane, and into the cytosol of the nociceptive sensory afferent cell wherein the Targeting Moiety is selected from the group consisting of BAM, β-endorphin, bradykinin, substance P, dynorphin and/or nociceptin.

主权项

1. A non-cytotoxic protein conjugate for inhibition or reduction of exocytic fusion in a nociceptive sensory afferent cell, comprising:
(i) a Targeting Moiety (TM),
wherein said TM binds to a Binding site on a nociceptive sensory afferent cell, wherein said Binding site undergoes endocytosis to be incorporated into an endosome within the nociceptive sensory afferent cell, and wherein the TM is nociceptin; (ii) a non-cytotoxic protease or a fragment thereof,
wherein the protease or protease fragment cleaves a protein of the exocytic fusion apparatus of said nociceptive sensory afferent cell and wherein the non-cytotoxic protease or fragment thereof is selected from a clostridial neurotoxin; and (iii) a Translocation Domain,
wherein the Translocation Domain translocates the protease or protease fragment from within the endosome, across the endosomal membrane, and into the cytosol of the nociceptive sensory afferent cell and wherein the Translocation Domain is a botulinum HN domain;wherein said conjugate comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:137, 138, 142, and 163-168.