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Synthesis and In Vitro Neuroprotective Activity of Glycine Analogs of Gk-2 Dimeric Dipeptide Mimetic of Nerve Growth Factor 4th Loopстатья
- Авторы: Sazonova N.M., Tarasyuk A.V., Firsova Yu N., Zvyagintsev A.A., Rebeko A.G., Antipov P.I., Nikolaev S.V., Antipova T.A., Gudasheva T.A.
- Журнал: Pharmaceutical Chemistry Journal
- Том: 54
- Номер: 2
- Год издания: 2020
- Издательство: Kluwer Academic/Plenum Publishers
- Местоположение издательства: United States
- Первая страница: 126
- Последняя страница: 133
- DOI: 10.1007/s11094-020-02168-0
- Аннотация: A dimeric dipeptide mimetic of nerve growth factor (NGF), bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), was previously developed at V. V. Zakusov State Institute of Pharmacology, activated specific TrkA receptors, and exhibited neuroprotective activity in vitro (10–5 – 10–9 M) and in vivo (0.1 – 10 mg/kg i.p. and p.o.). GK-2 was designed based on the beta-turn (-Asp94-Glu95-Lys96-Gln97-) of the NGF 4th loop and preserved the central dipeptide fragment (-Glu95-Lys96-). The Asp94 residue was replaced by its monosuccinyl bioisostere. The dimeric structure of NGF was reproduced using a bivalent hexamethylenediamine spacer. The structure—activity (neuroprotective) relationship for GK-2 was studied in the present work using a glycine scan, i.e., successive replacement of the peptide side groups by H. The bis-(N-acetyl-L-glutamyl-L-lysine) (GK-2Ac), bis-(N-monosuccinylglycyl-L-lysine) (GK-2-Gly1), and bis-(N-monosuccinyl-L-glutamylglycine) hexamethylenediamides (GK-2-Gly2) were less active with neuroprotective activity in vitro under oxidative stress for HT22 cells at concentrations 10 – 100 times greater than GK-2. The conclusion was drawn that each side radical of GK-2 was important for manifestation of the full neuroprotective activity of dimeric dipeptide GK-2, a mimetic of the NGF 4th loop. However, removal of any of the side radicals would probably not change the active structure of the beta-turn so that the two remaining side radicals should retain the ability to bind to their TrkA subsites. This could explain the retention of neuroprotective activity in the GK-2 glycine analogs.
- Добавил в систему: Николаев Сергей Владимирович