Peptide regulation of gene expression - a systematic review

Comprehensive systematic review by the Vladimir Khavinson group published in Molecules (MDPI), consolidating approximately five decades of research from the St. Petersburg Institute of Bioregulation and Gerontology on the mechanism of action of short peptide bioregulators. This article is the obligatory modern reference for any discussion of dipeptides and tetrapeptides from the Khavinson family — including Vesilute (Glu-Asp, ED), dipeptide proposed as a bioregulator of the bladder and urogenital tract.

The central thesis of the review is that short peptides (2-7 amino acids) directly penetrate the cell nucleus and nucleoli, where they interact with nucleosomes, histones, and DNA — both single- and double-stranded — at specific sequences in target gene promoters. This peptide-DNA interaction is proposed as the molecular mechanism underlying the tissue-specific activity of these compounds, distinguishing them from classical peptide hormones acting via surface receptors.

The review synthesizes experimental evidence in plants, microorganisms, insects, birds, rodents, primates and humans, suggesting that this peptide regulatory system is evolutionarily conserved and possibly acted as one of the earliest molecular signaling mechanisms. The authors propose that short peptides can regulate DNA methylation status — central epigenetic mechanism for gene activation or repression in physiological, pathological, and senescent conditions. Regulation would be mediated by peptide-chromatin interactions that alter transcriptional accessibility.

For Vesilute (Glu-Asp) specifically, the review provides the theoretical framework supporting the hypothesis of action in the urogenital tract — the ED sequence would be capable of modulating expression of genes relevant to bladder function, detrusor contractility, and tissue regeneration. Important limitations of the hypothesis remain: most primary evidence for Vesilute comes from Russian literature not fully available on PubMed; independent validation of the proposed mechanisms by Western laboratories remains limited; and most clinical studies are small and uncontrolled. This systematic review, however, offers the most complete and up-to-date theoretical foundation for the use of Vesilute in research.