Low-molecular mimetics of nerve growth factor and brain-derived neurotrophic factor: Design and pharmacological properties

To overcome the limitations of the clinical use of neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), scientists have been trying to create their low-molecular-weight mimetics having improved pharmacokinetic properties and lacking side effects of full-sized proteins since the 90s of the last century. The efforts of various research groups have led to the production of peptide and nonpeptide mimetics, being agonists or modulators of the corresponding Trk or p75 receptors that reproduced the therapeutic effects of full-sized proteins. This review discusses different strategies and approaches to the design of such compounds. The relationship between the structure of the mimetics obtained and their action mechanisms and pharmacological properties are analyzed. Special attention is paid to the dipeptide mimetics of individual NGF and BDNF loops having different patterns of activation of Trk receptors signal transduction pathways, phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase, which allowed to evaluate the contribution of each pathway to different pharmacological effects. In conclusion, data on therapeutically promising compounds being at different stages of preclinical and clinical studies are summarized.

Automated summary

This review discusses the efforts to create low-molecular-weight mimetics of neurotrophins NGF and BDNF with improved pharmacokinetic properties and lacking side effects. Various peptide and nonpeptide mimetics have been produced to mimic the therapeutic effects of full-sized proteins by targeting specific receptors. The relationship between the structure of these mimetics and their action mechanisms and pharmacological properties are analyzed, with special attention given to dipeptide mimetics and their activation of different signal transduction pathways. Promising compounds at different stages of preclinical and clinical studies are also summarized.