Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept.
This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.
State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia ; Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia.
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Vakhitova
Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia.
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Sadovnikov
Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia ; Ufa Institute of Chemistry RAS, Prospekt Oktyabrya, 71, 450065, Ufa, Russia.
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Borisevich
State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia.
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Ostrovskaya
State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia.
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A Gudasheva
State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia.
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Seredenin
HIF-1; HIF-prolyl hydroxylase 2; Noopept; docking; hypoxia; neuroprotection; transcriptional factors