Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor

• Published in: Neurochemistry international Vol. 61; no. 8; pp. 1266 - 1275
• Main Authors: Eibl, Joseph K., Strasser, Bridget C., Ross, Gregory M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2012
• Subjects: Analgesics - pharmacology; Analgesics - therapeutic use; Antagonist; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Clinical Trials as Topic; Crystallography, X-Ray; Humans; Ligands; Models, Molecular; Molecular Mimicry; Nerve Growth Factor - antagonists & inhibitors; Nerve Growth Factor - chemistry; Nerve Growth Factor - immunology; Nerve Growth Factor - physiology; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - physiology; Neurotrophin; NGF; Nociceptors - drug effects; Nociceptors - physiology; p75; Pain - drug therapy; Pain - physiopathology; Pain - prevention & control; Peptides - pharmacology; Protein Binding - drug effects; Protein Conformation; Receptor, trkA - antagonists & inhibitors; Receptor, trkA - physiology; Receptors, Nerve Growth Factor - antagonists & inhibitors; Receptors, Nerve Growth Factor - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Structure-Activity Relationship; Tanezumab; TrkA; Neurotrophin; TrkA; Antagonist; Tanezumab; NGF; p75
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2012.10.008

► NGF antagonism is the first novel class of pain therapeutic in the last 30years. ► The structural biology of NGF, p75NTR, and TrkA are reviewed in the context pharmacological target development. ► This article highlights the current state of therapeutic strategies for the targeting of NGF antagonists. ► The review provides a resource to summarize our current understanding of neurotrophin/receptor related structural biology. ► The review provides a comprehensive resource to summarize all reported NGF antagonists. Nerve growth factor (NGF) is critical for the development and maintenance of sympathetic and sensory neurons in the developing nervous system, including nociceptors. In the adult nervous system, NGF is known to produce significant pain signals by binding to the TrkA and p75NTR receptors. Several pathological pain disorders are associated with nerve growth factor dysregulation, including neuropathic pain, osteoarthritic pain, and hyperalgesia. Currently, clinical management of these pathologies has relied on the use of opioid and non-steroidal anti-inflammatory drugs (NSAID). However, several chronic pain conditions demonstrate insensitivity to NSAID treatment or the development of detrimental opioid-related side effects, including addiction. As NGF plays an important role in pain generation; antibodies, small molecules and peptides have been designed to antagonize NGF. In this review, we discuss the structural biology of NGF ligand/receptor interaction, and we review current biological and pharmacological strategies to modulate NGF-related pathologies.