Dimeric dipeptide mimetics of neurotrophins as molecular tools and potential neuroprotective drugs

Abstract

Proteins from the neurotrophin family perform trophic and regulatory functions in the nervous and other body systems. Understanding the mechanisms of neurotrophin action is crucial not only for the evolution of fundamental scientific knowledge but also for developing new treatment strategies targeting neurotrophin signaling regulation. At our center, dimeric dipeptide mimetics of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) have been obtained based on the structure of neurotrophins’ individual loops β-turns. These mimetics activated tyrosine kinase (Trk) receptors TrkA, TrkB, or TrkC specific to their respective neurotrophins, but exhibited varied activation patterns in the main post-receptor signaling cascades. Thus, some dipeptides activated all three main phosphoinositide 3-kinase (PI3K)/threonine-protein kinase (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phospholipase C-gamma (PLC-γ) pathways, while others triggered only PI3K/Akt and PLC-γ or MAPK/ERK and PLC-γ. Herewith, dipeptides exhibited a specific set of effects (neuroprotective, differentiating, antidepressant-like, anxiolytic, memory-enhancing, analgesic, antidiabetic) within the spectrum of biological activities of their corresponding native neurotrophin. It was revealed that these effects are influenced by both the patterns of post-receptor signaling activation and the nature of progenitor neurotrophin, uncovering significant correlations. This article is dedicated to reviewing the data that has been collected.

Keywords

• dimeric dipeptide mimetics
• bdnf
• ngf
• nt-3