Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept

Abstract

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.

Peptide Regulation of Gene Expression: A Systematic Review

“…For example, in the above-mentioned review [30], the description of the mechanism of the biological effects of peptides only touches on their ability to regulate gene expression. At the same time, as it was mentioned earlier, gene expression may be regulated by different mechanisms, DNA methylation, and/or histone acetylation, as well as transcription factors [27]. In the following, the authors will explore the mechanisms of peptide interaction with DNA and histones to explain the specificity of peptides' biological action.…”

“…There are very few studies in this area as compared, for example, to the considerable data available on the DNA methylation and/or histone acetylation, peptide binding with transcription factors, etc. [27]. However, studies of the patterns of DNA-peptide interactions identified in vitro help to characterize the specificity of action of short peptides.…”

The Dipeptide Pro-Gly Promotes IGF-1 Expression and Secretion in HepG2 and Female Mice via PepT1-JAK2/STAT5 Pathway

“…In addition, Pro-Gly significantly enhanced elastin synthesis of normal human dermal fibroblasts (NHDF) without affecting the rate of cell proliferation ( 32 ). Furthermore, Noopept (ethyl ester of N-phenylacetyl-L-prolylglycine), Pro-Gly-containing dipeptide, increased the DNA-binding activity of hypoxia-inducible factor 1 (HIF-1) in HEK293 cells ( 33 ). These results suggested the bioactive effects of the dipeptide Pro-Gly.…”