Small molecule and protein-based neurotrophic ligands: agonists and antagonists as therapeutic agents

Abstract

The neurotrophins are proteins of a growth factor family that affect the survival, growth and/or differentiation of neurones and several other populations derived from the neuroectoderm. Neurotrophins and their receptors are important targets for therapy of human disease, with potential applications ranging from treatment of chronic or acute neurodegeneration, to pain or cancer. Several neurotrophins have been used clinically. However, they are poor pharmacological agents because of drawbacks inherent to proteins when used as drugs. Consequently, several pharmacological agents and approaches have been patented to exploit these important targets. Amongst the pharmacological agents that do not act directly via neurotrophin receptors we include those that modulate or induce local expression of neurotrophins, immunophilins and other agents with neurotrophic-like activity. These are usually agonistic agents. Amongst compounds that bind to and act via neurotrophin receptors we include peptide analogues and peptidomimetics of neurotrophins of anti-neurotrophin receptor antibodies. These agents can be agonistic or antagonistic. Other approaches involve antagonists of the neurotrophins themselves, usually large receptor-derived peptides as decoy docking sites. Small molecule, non-peptide synthetic agonists and antagonists of either neurotrophins or neurotrophin receptors will be valuable therapeutic agents for diseases that have markets worth billions of US dollars. Consequently, it is not surprising that some patents have made similar claims both in compositions of matter and in indications.