Dr. Saragovi will discuss the concept of drug design and development, focussing on examples from his laboratory that have entered human clinical trials. His team has developed selective ligands of the neurotrophin receptors Trk or p75, targeting the ectodomain of the receptors. They developed small molecules as well as biopharmaceuticals. The ligands act as functional agonists or antagonists of the receptors ex vivo and in vivo. Using these ligands, they have validated the role of each of these receptors in animal models of disease. In neurodegeneration (age-associated cognitive impairment, Alzheimer's disease, neuropathy, ALS, and glaucoma) antagonists of p75 are protective, and agonists of Trk are protective. In cancer, they used the ligands for imaging tumor metastasis, and for the selective delivery of chemotherapeutics to receptor-expressing tumor cells.

Selected references
Ligand-dependent TrkA activity in brain impacts differently on spatial learning and long-term memory.
Aboulkassim T et al. (2011). Mol Pharmacol.  May 26. [Epub ahead of print]

Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism. Bai Y et al. (2010). J Biol Chem. 285:39392-39400. Epub 2010 Oct 13.

A neurotrophic rationale for the therapy of neurodegenerative disorders.
Saragovi HU et al. (2009). Curr Alzheimer Res. 6:419-423.

Host : Brian B. RUDKIN (bbrudkin@ens-lyon.fr)
*46, allée d’Italie, 69007 Lyon

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