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Design and Synthesis of Dipeptide Nerve Growth Factor Loop 1 Mimetics and In Vitro Studies of their Neuroprotective and Differentiation-Inducing Activitiesстатья
- Авторы: Tarasyuk A.V., Sazonova N.M., Rebeko A.G., Logvinov I.O., Nikolaev S.V., Antipova T.A., Gudasheva T.A., Seredenin S.B.
- Журнал: Pharmaceutical Chemistry Journal
- Том: 54
- Номер: 11
- Год издания: 2021
- Издательство: Kluwer Academic/Plenum Publishers
- Местоположение издательства: United States
- Первая страница: 1126
- Последняя страница: 1135
- DOI: 10.1007/s11094-021-02330-2
- Аннотация: Previous studies at the V. V. Zakusov Science Research Institute of Pharmacology created a dimeric dipeptide mimetic of the most exposed fourth loop of nerve growth factor (NGF), bis-(N-monosuccinyl-L-glutamyl-Llysine) hexamethylenediamide (GK-2), which activates specific TrkA receptors and has neuroprotective activity in vitro (at 105 to 109 M) and in vivo (0.1 – 10 mg/kg, i.p., or p.o.). The present report describes the construction and synthesis of a mimetic of the first loop of NGF based on the β-turn (-Lys32-Gly33-Lys34-Glu35-), bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6). The structure of GK-6 preserves the central dipeptide fragment of the β-turn -Gly33-Lys34-, the Lys32 residue being substituted by its bioisostere – a 6-aminocaproic acid residue - and the dimeric structure of NGF being reproduced by dimerization at the C-terminal using a bivalent hexamethylenediamine spacer. Structure-activity relationships of GK-6 were studied by sequential substitution of the side groups of the peptide by hydrogen to produce bis-(N-acetyl-glycyl-Llysine) hexamethylenediamide (GTS-611) and bis-(N-aminocaproyl-glycyl-glycine) hexamethylenediamine (GTS-613). Mimetic GL-6 and its analogs GTS-613, which contains the N-aminocaproyl radical, had neuroprotective effects at concentrations of 106 and 105M in conditions of oxidative stress in HT-22 neuron cultures. Dipeptide GTS-611, in which the aminocaproyl fragment was replaced by an acetyl residue, had no neuroprotective activity in these conditions, pointing to the importance of Lys32 in NGF for this property. In contrast to the loop 4 mimetic GK-2, the loop 1 mimetics GK-6 and GTS-611 showed differentiation-inducing activity on PC12 cells.
- Добавил в систему: Николаев Сергей Владимирович