Peptides as epigenetic modulators: therapeutic implications

Abstract

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.

PaDef (Persea americana var. drymifolia), a Plant Antimicrobial Peptide, Triggers Apoptosis, and Induces Global Epigenetic Modifications on Histone 3 in an Acute Lymphoid Leukemia Cell Line

“…It has been shown that plant AMPs can play a role as epigenetic modulators in cancer cells ( Arceo-Martínez et al, 2018 ; Janssens et al, 2019 ). To evaluate whether the cytotoxic effect of PaDef was related to epigenetic modifications, we explored some epigenetic marks of Histone 3 (H3).…”

“…Noteworthy, some AMPs are not toxic to normal mammalian cells and have a broad spectrum of cytotoxic activity on tumor cells. Also, it has been described the epigenetic modulation of AMPs related to anticancer activities, as is the case of lunasin, a peptide derived from soy that inhibits the acetylation of Histone 3 and 4 ( Wan et al, 2017 ; Janssens et al, 2019 ). This fact increases the relevance of the study of AMP as an attractive source of new therapies against cancer.…”

Epigenetic signature in neural plasticity: the journey so far and journey ahead

“…Several factors, including food, microbiota, physical activities, and environmental pollutants can largely influence epigenetic changes. Epigenetic modifications can also affect one another by adding extra layers of epigenetic regulation [ 53 ]. Epigenetic processes being reversible and labile, are regulated by different signature proteins or molecules.…”

Reviewing cancer’s biology: an eclectic approach

“…The third and last class, i.e., the epigenetic modulators, are tissues-specific proteins vital to normal cellular functions as they lead the cell and tissue differentiation mechanisms. They transmit environmental signals to the epigenetic modifiers [151][152][153][154] DNA methylation DNA methylation is one of commonest studied and well-characterized among the changes. The process involves transferring a methyl group to position 5′ of the pyrimidine-cytosine of 5′-CpG-3′-rich DNA regions called CpG islands: a palindromic set of cytosine-phosphate-guanine dinucleotides found in the promoter region and other genomic regions.…”