2015
DOI: 10.1186/s12929-015-0198-z
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Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction

Abstract: BackgroundThis study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), were designed based on the most exposed outside fragments of NGF, namely, the loop 1 and loop 4 β-turn sequences, respectively. These dipeptides exhibited neur… Show more

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Cited by 50 publications
(45 citation statements)
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“…The mimetic of BDNF loop 4 GSB-106 increased the levels of ERK and AKT kinase phosphorylation, whereas the mimetic of BDNF loop 1 GSB-214 increased the level of AKT phosphorylation only. Notably, dimeric dipeptide mimetics of nerve growth factor (NGF) loops 1 and 4 demonstrated the opposite patterns of post-receptor signal transduction, as we reported earlier 19. The mimetic of NGF loop 4, bis -(N-succinyl- l -glutamyl- l -lysine) hexamethylenediamide (GK-2), selectively activated the PI3K/AKT signaling pathway, while the mimetic of NGF loop 1, bis -(N-aminocarbonyl-glycyl- l -lysine)hexameth-ylenediamide (GK-6), activated both the PI3K/AKT and MAPK/ERK pathways 19…”
Section: Discussionsupporting
confidence: 57%
“…The mimetic of BDNF loop 4 GSB-106 increased the levels of ERK and AKT kinase phosphorylation, whereas the mimetic of BDNF loop 1 GSB-214 increased the level of AKT phosphorylation only. Notably, dimeric dipeptide mimetics of nerve growth factor (NGF) loops 1 and 4 demonstrated the opposite patterns of post-receptor signal transduction, as we reported earlier 19. The mimetic of NGF loop 4, bis -(N-succinyl- l -glutamyl- l -lysine) hexamethylenediamide (GK-2), selectively activated the PI3K/AKT signaling pathway, while the mimetic of NGF loop 1, bis -(N-aminocarbonyl-glycyl- l -lysine)hexameth-ylenediamide (GK-6), activated both the PI3K/AKT and MAPK/ERK pathways 19…”
Section: Discussionsupporting
confidence: 57%
“…ГК-2 проявлял выраженные терапевтические эффекты на разных моделях ишемии головного мозга [7]. При этом ГК-2 не обладал побочными эффектами, характерными для полноразмерного белка, а именно не вызывал гипералгезии и потери веса при длительном введении в наиболее эффективной дозе [8]. Кроме того, ГК-2 продемонстрировал нейропротективную активность in vivo в дозах 0,01-5 мг/кг внутрибрюшинно и 5-10 мг/кг перорально на ряде моделей болезней Альцгеймера, Паркинсона и сахарного диабета [6].…”
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“…As previously mentioned, reduced synthesis of NGF and impaired reverse axoplasmic transport may be potential causes of PDN and the down-regulation of NGF expression in dorsal horn and DRG. We knew that exogenous NGF could increase the NGF expression in the target tissues (7) and repair the damaged axonal retrograde transport through the activation of PI3/Akt and MAPK/ERK signal pathway (33). Therefore, in the present study, the NGF expression in dorsal horn and DRG increased to different levels after the treatment of exogenous mNGF.…”
Section: E559mentioning
confidence: 51%