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Retargeted clostridial endopeptidases: Inhibition of nociceptive neurotransmitter release in vitro, and antinociceptive activity in in vivo models of pain
Author(s) -
Chaddock John A.,
Purkiss John R.,
Alexander Frances C.G.,
Doward Sarah,
Fooks Sarah J.,
Friis Lorna M.,
Hall Yper H.J.,
Kirby Elizabeth R.,
Leeds Nicola,
Moulsdale Hilary J.,
Dickenson Anthony,
Green G. Mark,
Rahman Wahida,
Suzuki Rie,
Duggan Michael J.,
Quinn Conrad P.,
Shone Clifford C.,
Foster Keith A.
Publication year - 2004
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.20008
Subject(s) - in vivo , pharmacology , neurotoxin , in vitro , neurotransmitter , chemistry , nociception , biochemistry , biology , receptor , microbiology and biotechnology
Clostridial neurotoxins potently and specifically inhibit neurotransmitter release in defined cell types. Previously reported data have demonstrated that the catalytically active LH N endopeptidase fragment of botulinum neurotoxin type A (termed LH N /A) can be retargeted to a range of cell types in vitro to lead to inhibition of secretion of a range of transmitters. Here, we report the synthesis of endopeptidase conjugates with in vitro selectivity for nociceptive afferents compared to spinal neurons. Chemical conjugates prepared between Erythrina cristagalli lectin and LH N /A are assessed in vitro and in in vivo models of pain. Chemical conjugates prepared between E. cristagalli lectin and either natively sourced LH N /A, or recombinant LH N /A purified from Escherichia coli are assessed, and equivalence of the recombinant material is demonstrated. The duration of action of inhibition of neurotransmitter release by the conjugate in vitro is also assessed and is comparable to that observed with Clostridium botulinum neurotoxin. Selectivity of targeting and therapeutic potential have been confirmed by in vivo electrophysiology studies. Furthermore, the analgesic properties of the conjugate have been assessed in in vivo models of pain and extended duration effects observed. These data provide proof of principle for the concept of retargeted clostridial endopeptidases as novel analgesics. © 2004 Movement Disorder Society