Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-08-07
2000-01-25
Allen, Marianne P.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530399, 530317, A61K 3812, C07K 764
Patent
active
060178787
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The invention relates to cyclic compounds having a 3-dimensional structure which binds to neurotrophin receptors, their uses for the treatment or prevention of peripheral and central nervous system diseases, neuromas at the end of an amputated limb and neoplastic diseases which express neurotrophin receptors.
(b) Description of Prior Art
Nerve Growth Factor (NGF) is a protein which has prominent effects on developing sensory and sympathetic neurons of the peripheral nervous system and cholinergic neurons of the CNS. NGF is a polypeptide growth factor member of the neurotrophin family, which includes Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT3) and Neurotrophin-4/5 (NT-4/5). NGF controls the survival and development of certain neuronal populations and has been reported to be a mitogen for other cell types. Two cell surface NGF receptors have been characterized on the basis of binding affinity and signal transduction properties, namely the p75 low affinity NGF receptor (LNGFR) and p140 trkA.
The p75 receptor (Kd=10.sup.-9 M; Johnson, D. et al. (1986) Cell, 47: 545-554) is a 75 kDa glycoprotein member of the TNFR/Fas/CD40 family of receptors (Itoh et al., (1991) Cell, 66:233-243). p75 contains no intrinsic catalytic activity but can associate with the ERK family of soluble kinases (Volonte C. et al. (1993) J. Biol. Chem., 268:21410-21415), and plays a role in protection from neuronal apoptotic death (Rabizadeh, S. et al. (1993) Science, 261:345-348). p75 is also the low affinity binding receptor for BDNF and NT-3 (Ibanez, C. F. et al. (1991) Eur. Mol. Biol. Org. J., 10:2105-2110) but these latter growth factors each have distinct trk receptors.
The p140 trkA receptor is a 140 kDa glycoprotein encoded by the trk proto-oncogene (Klein, R. et al. (1991) Cell, 65:189-197). Scatchard analysis of cells expressing only trkA receptors showed a curvilinear plot with Kd .sup..about. 10.sup.-11 M and 10.sup.-9 M (Jing, S. et al. (1992) Neuron, 9: 1067-1079). The trkA receptor has intrinsic tyrosine kinase activity and is capable of evoking cellular neurotrophic responses in vitro in the absence of p75 LNGFR (Hempstead, B. L. et al. (1991) Nature, 350: 678-683).
The co-expression of both p75 and p140 allows detection of a higher affinity NGF receptor and affords a Kd .sup..about. 10.sup.-12 M (Jing, S. et al. (1992) Neuron, 9: 1067-1079). Hence, p75 can associate with different trk-receptors to form high affinity binding sites but neurotrophin binding specificity is mediated by distinct trk-receptors (Ip, N.Y. et al. (1993) Neuron, 10:137-149). The molecular nature of the functional receptor remains unknown.
The NGF protein has been purified, cloned and sequenced (Angeletti, R. H. et al. (1973) Biochemistry, 12: 100-115). Cloning of NGF from different species has shown high amino acid sequence homology, and cross-species biological reactivity.
The structure of mouse NGF has been resolved from crystallographic data at 2.3 .ANG. resolution (McDonald, N. Q. et al. (1991) Nature, 345: 411-414). In the crystals, the NGF molecule is a tightly associated dimer made up of parallel protomers of 118 amino acids. Each protomer has seven .beta.-strands forming three antiparallel pairs. The .beta.-strands are linked by four exposed regions: three .beta.-turns (termed A'-A", A'"-B, and C-D) and one series of three contiguous reverse-turns (termed B-C).
The .beta.-turn and reverse-turn regions had been noted for their hydrophilic nature and unlike the mostly conserved buried residues of the .beta.-strands the .beta.-turns have little conservation between different neurotrophins (Hallbook, F. et al. (1991) Neuron, 6: 845-858). The variability and hydrophilicity of these .beta.-turn regions has prompted the hypothesis that they may be involved in determining neurotrophin receptor specificity because several dimeric molecules use .beta.-turns for critical binding surface(s). Similarly, antibodies and other members of the immunoglobulin gene superfamily (Chothia, C.
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Cuello Claudio A.
Lesauteur Lynne
Saragovi Uri H.
Allen Marianne P.
McGill University
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