Mechanism of biological activity of short peptides: Cell penetration and epigenetic regulation of gene expression

Хавинсон, В Х; Solov’ev, A. Yu.; Tarnovskaya, S. I.; Linkova, N. S.

doi:10.1134/s2079086413060042

Cited by 20 publications

(11 citation statements)

References 25 publications

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“…Previous investigations have shown that short peptides especially those which include positively charged lysine or arginine may penetrate into the cell and nucleus and probably bind to the DNA [24,25]. So, peptide KEDW (Lys-Glu-Asp-Trp-NH2) is able to reduce the blood glucose level in rats with streptozotocin-and alloxan-induced diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

“…As an example, myelopeptide-4 has been shown to bind on the HL-60 cell surface, to penetrate into their cytoplasm, and finally to concentrate around the cell nucleus [23]. Recently it was shown that peptide EDR linked with СNG-containing de-oxyribooligonucleotides (preferably CAG-containing structures), making these sites unavailable to DNA methyltransferases, whereby the promoter was unmethylated [24,25].…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effect of EDR Peptide in Mouse Model of Huntington's Disease

Хавинсон¹,

Линькова²,

Kukanova³

et al. 2017

J Neurol Neurosci

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Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder. The study in functioning and aging of neurons may give an opportunity to regulate these processes. Previous investigations demonstrated the ability of EDR peptide (Glu-Asp-Arg) to penetrate a cell nucleus and stimulate gene expression. The data obtained prompt EDR peptide capability to restore the morphology of spines in striatum neurons in Huntington's disease (HD) mouse model. EDR peptide has been shown by us to bind the DNA in solution (absorption spectroscopy and dynamic light scattering) and in a computer model. The proposed model suggests that EDR peptide binds specific binding site oligo (dCG) along the DNA minor groove.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of EDR Peptide in Mouse Model of Huntington's Disease

Хавинсон¹,

Линькова²,

Kukanova³

et al. 2017

J Neurol Neurosci

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“…If this is the case, then these short peptides of four amino acids and less can be considered as a separate class of epigenetic regulators. Another proposed mechanism of action is the binding of these peptides to the gene promotor region making it inaccessible for DNA methyltransferases, resulting in unmethylated promotor regions and gene activation [59, 60]. This way, the short peptides act as DNA methylation inhibitors (Fig.…”

Section: The Influence Of Peptides On Epigenetic Mechanismsmentioning

confidence: 99%

Peptides as epigenetic modulators: therapeutic implications

2019

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Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation. Endogenous short peptides, resulting from proteolytic cleavage of proteins or upon translation of non-annotated out of frame transcripts, can block DNA methylation and hereby regulate gene expression. Peptides entering the body by digestion of food-related proteins can modulate DNA methylation and/or histone acetylation while environmental peptides, synthesized by bacteria, fungi, and marine sponges, mainly inhibit histone deacetylation. In addition, synthetic peptides that reverse or inhibit different epigenetic modifications of both histones and the DNA can be developed as well. Next to these DNA and histone modifications, peptides can also influence the expression of non-coding RNAs such as lncRNAs and the maturation of miRNAs. Seen the advantages over small molecules, the development of peptide therapeutics is an interesting approach to treat diseases with a strong epigenetic basis like cancer and Alzheimer’s disease. To date, only a limited number of drugs with a proven epigenetic mechanism of action have been approved by the FDA of which two (romidepsin and nesiritide) are peptides. A large knowledge gap concerning epigenetic effects of peptides is present, and this class of molecules deserves more attention in the development as epigenetic modulators. In addition, none of the currently approved peptide drugs are under investigation for their potential effects on epigenetics, hampering drug repositioning of these peptides to other indications with an epigenetic etiology.

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“…Apart from mAbs specifically targeting tumor antigens, receptors and co-signaling molecules of the immune system, bioactive peptides from a number of sources have been studied with various specificities and affinities for microorganisms and eukaryotic cells (12,13). For more than a decade, peptides derived from immunoglobulin (Ig) internal sequences have been shown to display differential anti-infective and anti-tumor activities in vitro and in vivo (14,15).…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Protective Effects of Rb9 Cyclic-Peptide in a Metastatic Melanoma Setting and the Involvement of Dendritic Cells

et al. 2020

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The cyclic VHCDR3-derived peptide (Rb9) from RebMab200 antibody, directed to a NaPi2B phosphate-transport protein, displayed anti-metastatic melanoma activity at 50-300 µg intraperitoneally injected in syngeneic mice. Immune deficient mice failed to respond to the peptide protective effect. Rb9 induced increased CD8+ T and low Foxp3+ T cell infiltration in lung metastases and high IFN-γ and low TGF-β in lymphoid organs. The peptide co-localized with F-actin and a nuclear site in dendritic cells and specifically bound to MIF and CD74 in a dot-blot setting. Murine bone-marrow dendritic cells preincubated with Rb9 for 6 h were treated with MIF for short time periods. The modulated responses showed stimulation of CD74 and inhibition of pPI3K, pERK, and pNF-κB as compared to MIF alone. Rb9 in a melanoma-conditioned medium, stimulated the M1 type conversion in bone marrow-macrophages. Functional aspects of Rb9 in vivo were studied in therapeutic and prophylactic protocols using a melanoma metastatic model. In both protocols Rb9 exhibited a marked anti-melanoma protection. Human dendritic cells were also investigated showing increased expression of surface markers in response to Rb9 incubation. Rb9 either stimulated or slightly inhibited moDCs submitted to inhibitory (TGF-β and IL-10) or activating (LPS) conditions, respectively. Lymphocyte proliferation was obtained with moDCs stimulated by Rb9 and tumor cell lysate. In moDCs from cancer patients Rb9 exerted immunomodulatory activities depending on their functional status. The peptide may inhibit over-stimulated cells, stimulate poorly activated and suppressed cells, or cause instead, little phenotypic and functional alterations. Recently, the interaction MIF-CD74 has been associated to PD-L1 expression and IFN-γ, suggesting a target for melanoma treatment. The effects described for Rb9 and the protection against metastatic melanoma may suggest the possibility of a peptide reagent that could be relevant when associated to modern immunotherapeutic procedures.

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Mechanism of biological activity of short peptides: Cell penetration and epigenetic regulation of gene expression

Cited by 20 publications

References 25 publications

Neuroprotective Effect of EDR Peptide in Mouse Model of Huntington's Disease

Neuroprotective Effect of EDR Peptide in Mouse Model of Huntington's Disease

Peptides as epigenetic modulators: therapeutic implications

Immunomodulatory Protective Effects of Rb9 Cyclic-Peptide in a Metastatic Melanoma Setting and the Involvement of Dendritic Cells

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