3AA Preclinical
Ovagen
Porcine liver-derived synthetic tripeptide bioregulator (Glu-Asp-Leu) that targets hepatocyte gene expression to reduce fibrosis, restore detoxification capacity, and protect the GI mucosal barrier.
In Plain English:
Ovagen is a three-amino-acid chain (Glutamic acid – Aspartic acid – Leucine, abbreviated EDL) originally derived from compositional analysis of young porcine liver tissue and then synthesised as the defined Cytogen-class bioregulator. Like other Khavinson peptides, it is ultrashort enough to pass through cell membranes and enter the nucleus via PEPT1/PEPT2 transporters, where it binds DNA in a sequence-specific way and nudges gene expression back toward youthful patterns. In aged hepatocyte cultures, it raised proliferation marker Ki-67 and lowered the senescence/apoptosis markers p16, p21, and p53 while increasing SIRT-6, consistent with a shift away from cellular ageing. Animal models of CCl₄- and paracetamol-induced hepatotoxicity show normalisation of ALT/AST, reduced oxidative-stress markers, and improved histological liver structure. A 2014 PubMed study (PMID 25946838) used EDL alongside AED in renal cell cultures and confirmed DNA-binding in the minor groove by molecular modelling. The 2021 Khavinson systematic review (PMID 34834147, PMC 8619776) explicitly lists EDL with hepatoprotection as a documented biological function. Clinical use in Russia covers hepatitis of various aetiologies, toxic and alcoholic liver damage, GI mucosal recovery post-chemotherapy or antibiotics, and biliary dyskinesia. No controlled human RCT has been published; the evidence base is preclinical plus observational Russian clinical experience.
Research Maturity
Preclinical (~6–10 peer-reviewed papers (2007–2021) on EDL/Ovagen; single research group, no RCTs or independent replication+ Studies)
Focus
Inflammation Modulation
Liver Support
Systemic Recovery
Origin
Developed by Professor Vladimir Kh. Khavinson and colleagues at the St. Petersburg Institute of Bioregulation and Gerontology as part of the Cytogen (synthesised peptide) programme. Compositional analysis of young porcine liver tissue identified the tripeptide Glu-Asp-Leu as the active regulatory core. Marketed under the trade name Ovagen® by GARMONIA Ltd (Russia, UPC 4603423002161); the EU-registered Cytogen distributor is SIA 'NPCRIZ Europe', Latvia (Reg. Nr. LV40203087850). First patent reference for hepatocyte proliferation data: Khavinson et al., 2007 (cited in Core Peptides research article).
Mechanism
Enters hepatocytes and GI epithelial cells via POT-family oligopeptide transporters PEPT1 and PEPT2, which recognise di- and tripeptides with high selectivity. Inside the nucleus, EDL docks in the minor groove of DNA through sequence-dependent hydrogen-bond and electrostatic interactions (molecular modelling confirmed for AED/EDL family; PMID 25946838). Key downstream effects: (1) Chromatin decondensation — reduces hypermethylation and heterochromatin compaction in aged liver fibroblasts, restoring gene transcription availability. (2) Cell-cycle regulation — lowers expression of p16, p21, and p53 while increasing SIRT-6, shifting the balance from senescence toward proliferation in aged renal and inferred hepatic cells. (3) Antioxidant upregulation — activates Nrf2-mediated antioxidant response (SOD, glutathione peroxidase, glutathione-S-transferase) while suppressing NF-κB pro-inflammatory signalling. (4) Anti-apoptotic — reduces caspase-3 expression. (5) mTOR activation — the leucine residue promotes mTOR pathway signalling, supporting anabolic and regenerative metabolism. (6) Anti-fibrotic gene expression — activates programmes opposing hepatic stellate-cell activation and collagen deposition, limiting scarring. Net tissue effect: normalisation of hepatocyte proliferation/apoptosis balance, reduction of oxidative stress, and protection of GI mucosal integrity.
Outcome
In aged human liver fibroblast cultures: 18-fold increase in Ki-67 proliferation marker; 6-fold decrease in p53 apoptosis marker (Jay Campbell, citing Khavinson laboratory data). In renal cell cultures treated with EDL/AED (PMID 25946838, 2014): increased Ki-67, decreased p16/p21/p53, increased SIRT-6 in both young and aged cells; molecular modelling confirmed minor-groove DNA binding. In CCl₄-hepatotoxicity rat models: significant reduction in ALT and AST liver enzyme levels; reduced oxidative-stress markers; improved liver histology with decreased necrosis and inflammatory infiltration (Khavinson et al., 2012, cited preclinically). In paracetamol-hepatotoxicity models: normalisation of hepatocyte structure and antioxidant status. Russian observational clinical experience (hepatitis patients): stabilisation of bilirubin and ALT/AST biochemical indices; reduced weakness and fatigue. HIV-1 protease inhibition in vitro: Ki ≈ 50 µM competitive inhibitor (Louis et al., ACS 1998 — mechanistic curiosity, not a therapeutic application). Systematic review 2021 (PMID 34834147): EDL listed as exhibiting 'hepatoprotection' and 'regulation of renal cells' function' among documented biological activities of Khavinson tripeptide family.
