Discovery of novel ligands of the high affinity NGF receptor Trk-A

Neurotrophins are a family of cytokines that regulate growth, development, and survival of neural cells, as well as a growing number of disparate cell types. The molecular structures responsible for the conveyance of biologic signal of neurotrophins inside the responding cells are a group of receptors, with low and high affinity for the extra cellular ligand. Receptor proteins nbelonging to the family of tropomyosin kinases (Trk), bind neurotrophins in a highly specific manner: Trk-A binds Nerve Growth Factor (NGF), Trk-B binds Brain-Derived Neurotrophic Factor (BDNF), Trk-C binds NT-3/4. Many studies focussed on neurotrophins and their receptors because abnormal neurotrophin actions are involved in neurodegenerative disorders such as Alzheimer Disease, Parkinson Disease and even cancer. Unfortunately, neurotrophins themselves, like most proteins, present unfavourable pharmacologic properties and can hardly be used as drugs, because of their sensitivity to proteolysis, restricted penetration of central nervous system and expensive production. Therefore small molecules able to interact with the neurotrophin receptors, either as agonists or antagonists, are of great interest for many therapeutic applications and could represent the suitable solution for stability to proteolysis and specificity in receptor binding, the two main concerns in drug design. The potential applications of such small molecules could be the treatment of acute or chronic neurological disorders (such as stroke and Alzheimer disease), cutaneous pressure ulcers, and corneal neurotrophic ulcers. In fact, NGF, beyond induction of cell differentiation, is critically involved in control of the survival/apoptosis divide. Peptidomimetic structures represent a useful tool in drug discovery, since modifications of bioactive peptides can result in better pharmacological properties like higher metabolic stability, increased bioavailability and higher receptor affinity or selectivity.