Research Dossier on Vesugen

(KED; Lys–Glu–Asp)

(Bioregulator Peptide)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

Vesugen is a synthetic ultrashort tripeptide with the sequence Lys–Glu–Asp (KED). Analytical entries list a molecular formula of C₁₅H₂₆N₄O₈ and molecular weight ≈ 390.39 g·mol⁻¹ (free acid). The tripeptide is strongly polar/ionic (one basic and two acidic residues), which influences aqueous solubility and favors electrostatic interactions with polyanionic DNA and acidic protein surfaces in docking models (see Mechanisms). Commercial research-grade listings corroborate the sequence and formula and cross-reference PubChem CID 87571363. canlabintl.com+1

Although Vesugen is frequently described as a vascular wall–derived motif, it is not a direct fragment of a single endogenous protein; rather, it belongs to the family of organ-specific “peptide bioregulators” developed by the Russian school of short-peptide research (Khavinson and colleagues). Within that taxonomy, KED is attributed to the vascularsystem and is often grouped with other 2–4-mer peptides such as AEDG (Epitalon), EDR (Pinealon), KE (Thymogen), and KED (Vilon), each investigated for tissue-directed regulatory activity in vitro/in vivo. PMC

Discovery history (lab, year, species)

Work on organ-specific short peptides dates to the late 20th century in the USSR/Russia, where peptide fractions were refined, and defined short sequences were synthesized to probe gene-regulatory and cell-protective effects. In English-language, peer-reviewed sources, Vesugen/KED appears in mechanistic and small translational studies from the 2010s onward, focused on vascular endothelium and cell-aging paradigms. PubMed

Endogenous vs synthetic origin

• Endogenous: There is no evidence that Lys–Glu–Asp circulates as a discrete endogenous hormone.

• Synthetic (research-grade): Vesugen is manufactured by solid-phase peptide synthesis; most bench studies use H-Lys-Glu-Asp-OH with ≥95% purity (HPLC/MS identity typically reported in methods). canlabintl.com

Homologs, analogs, derivatives

• Vilon (Lys–Glu)—a dipeptide frequently used as a vascular/immune comparator.

• Pinealon (Glu–Asp–Arg; EDR)—a tripeptide investigated in neuronal and oxidative-stress models.

• Epitalon (Ala–Glu–Asp–Gly; AEDG)—a tetrapeptide linked to chromatin and telomere pathways in cell/invertebrate models.
  These homologs often appear alongside KED in comparative studies on dendritogenesis, antihypoxic effects, and gene-promoter docking. PMC+1

Historical Development & Research Trajectory

Key milestones in discovery and study

1. Epigenetic/gene-promoter studies (2014): In vascular endothelial cell cultures from young and old animals, KEDincreased Ki-67 expression (a proliferation marker), and molecular docking suggested direct interaction with the MKI67 (Ki-67) promoter region—one of the earliest English-abstracted mechanistic links between Vesugen and cell-cycle gene regulation. PubMed

2. Antihypoxic stress (2008): In a hypobaric hypoxia model, Vesugen, Pinealon (EDR), Epitalon (AEDG) and Vilon (KE) all displayed antihypoxic activity; EDR was strongest, but KED showed protective trends, supporting a shared stress-response motif among short peptides. PubMed

3. Cellular aging/induced neurons (2024): In human fibroblast-derived induced neurons, panels of short peptides—including Vesugen/KED—partially protected against age-associated phenotypes and stimulated dendritogenesis (spine metrics, neurite outgrowth), extending prior AD-model spine data to a human-derivedcellular system. PMC

4. Human geropreventive pilot (2015): An open-label study (n=32, age 41–83) reported that Pinealon and Vesugencourses improved biological-age indices (CNS-related composite metrics), with Vesugen showing somewhat larger effects; however, the same study noted pro-oxidant chemiluminescence signals and decreases in CD34⁺ hematopoietic cells—an ambiguous safety/PD signature requiring caution and replication. PubMed

5. Urologic microvascular pilot (2014): In men with vasculogenic erectile dysfunction, a Russian-language study (English abstract) examined Vezugen as a vasoactive tripeptide adjunct; methodology details are sparse, but the report underscores Vesugen’s vascular positioning. PubMed

Paradigm shifts & controversies

• From vasoprotective “bioregulator” to gene-targeting micro-ligand. The research language evolved from broad vascular bioregulation to promoter-level hypotheses where short peptides dock to DNA/RNA motifs and modulate transcription/translation of cell-cycle and stress genes—provocative, but not yet proven by gold-standard in vivo chromatin assays for KED. PubMed

• Evidence quality & generalizability. A substantial fraction of Vesugen work originates from a limited set of laboratories; many clinical-style reports are small, open-label, or non-randomized. Independent multicenter replication under contemporary CONSORT standards remains limited. PubMed

Evolution of scientific interest

The thematic arc has moved from vascular endothelium (Ki-67/proliferation) → hypoxia tolerance → neuroplasticity/dendritic spines (aging and AD-adjacent cell models) → small pilot human studies in aging, with exploratory clinical signals counter-balanced by safety/hematopoietic questions that remain open. PubMed+2PubMed+2

Mechanisms of Action

Primary and secondary receptor interactions

No canonical cell-surface receptor has been identified for KED. The working hypotheses in peer-reviewed reports include:

1. Nucleic-acid docking (promoter-level “micro-ligand” action). Molecular docking suggested that KED can bind the MKI67 promoter and enhance expression of Ki-67, a proliferation index suppressed with vascular aging. While in silico and in-vitro correlations are intriguing, direct proof of in vivo promoter occupancy (e.g., peptide-ChIP with orthogonal validation) is Not established. PubMed

2. Chromatin & epigenetic modulation (class-level). Reviews of short peptides (including KED) posit sequence-specific interactions with DNA/RNA and histone or transcription factor complexes, enabling tissue-selectivechanges in gene programs (e.g., proliferation, cytoprotection). Such class claims are supported by several peptide exemplars, but mechanistic granularity for KED per se is incomplete. PMC

3. Membrane/cytoplasmic signaling interfaces. Given the peptide’s size/charge, endocytosis or transporter-mediated uptake into endothelial or neuronal cells is plausible; downstream effects (ERK/MAPK, redox enzymes) are inferred, not mapped comprehensively for KED.

Evidence grading (mechanism):

• A: KED increases Ki-67 expression and proliferation metrics in vascular endothelial cultures; docking supports proximity to MKI67 promoter. PubMed

• B: Class-level peptide-DNA interaction and neuronal dendritogenesis effects (human iNeurons) provide biological plausibility. PMC

• C: Direct identification of primary targets, binding constants, and in vivo promoter engagement for KED are Not established.

Intracellular signaling pathways

• Cell-cycle/proliferation: Up-regulation of Ki-67 (MKI67), a marker critical for cycling cells (G1, S, G2, M), suggests that KED can re-activate proliferation programs in senescent or aged vascular endothelial cells. PubMed

• Antihypoxic defenses: In hypobaric models, short peptides (including KED) reduced hypoxia-induced damage; downstream redox and mitochondrial pathways (e.g., Nrf2, ROS scavenging) are postulated but not fully delineated for KED. PubMed

• Neuroplasticity: In AD-relevant and aging models, short peptides (including KED) increased dendritic spine density/dendritogenesis, implying effects on cytoskeletal dynamics, synaptic gene sets (e.g., calmodulin/CaMKII, PSD-95 networks), or CREB signaling; precise KED-specific pathway maps remain incomplete. PMC

CNS vs peripheral effects

• Peripheral (vascular/endothelial)—the strongest mechanistic footprint (Ki-67, endothelial proliferation).

• CNS—emerges from aging/AD cell models and induced neuron work; direct in vivo CNS pharmacology for KED is limited.

Hormonal, metabolic, immune interactions

Published studies do not demonstrate direct endocrine receptor activity for KED. In limited immune-cell work from the short-peptide literature, KED has been associated with proliferation of specific cell subsets or no effect in context-specific assays (e.g., pineal immune cells: increased proliferation but not differentiation). PubMed

Pharmacokinetics & Stability

ADME profile

Human PK for Lys–Glu–Asp is not reported in peer-reviewed English-language sources. By analogy to other 2–4-merpeptides:

• Absorption: Parenteral administration is expected to yield rapid systemic exposure; oral bioavailability is typically low for free peptides of this size (unless protected). Intranasal transport has not been documented for KED. Status: Not established.

• Distribution: With Mr ≈ 390 g·mol⁻¹, KED likely partitions to extracellular fluid and is filtered readily by the kidney. Tissue uptake (endocytosis/transporter) is plausible but unquantified. Status: Not established.

• Metabolism: Exopeptidases and endopeptidases degrade short peptides to constituent amino acids; half-life is typically minutes to tens of minutes unless stabilized. Status: Not established for KED specifically.

• Elimination: Expected renal clearance of intact/fragment peptides; no human t½ reported. Status: Not established.

Plasma half-life & degradation pathways

No validated t½ for KED in mammals has been published in English; the short-peptide class is generally short-livedunless encapsulated/modified. Status: Not established.

Stability in vitro & in vivo

In cell studies, KED remains bioactive across typical incubation windows (hours). In vivo stability has not been quantified in peer-reviewed English sources. Status: Not established.

Storage/reconstitution considerations

Peer-reviewed CMC data are sparse. Research suppliers typically provide HPLC/MS certificates and recommend −20 °Cdry storage; solution stability depends on pH, buffer, and microbial control (vendor-specific).

Preclinical Evidence

Vascular endothelial biology & epigenetic regulation

• Ki-67 restoration in aging endothelium. In tissue-specific cell cultures and dissociated vascular endothelialcultures from young and old animals, Vesugen/KED increased Ki-67 protein—reduced with age—implicating partial rejuvenation of proliferative capacity. Docking suggested KED–DNA contacts at the MKI67 promoter, consistent with transcriptional activation. Concentration/time details follow cell-biology norms; doses varied by experiment. PubMed

• Gene-regulatory review (systematic). A comprehensive review of peptide regulation of gene expressioncatalogs short peptides, including KED, as putative sequence-specific DNA/RNA ligands that fine-tune transcription/translation in tissue-specific fashion; while the review compiles many datasets, it also acknowledges remaining gaps in target validation. PMC

Antihypoxic properties

• In a hypobaric hypoxia model, KED (with EDR, AEDG, KE) showed antihypoxic activity; EDR appeared strongest, but KED was protective vs controls—supporting a stress-response role across the short-peptide panel. Investigational dosing used in study: the paper reports experimental injection schedules for each peptide in rodents; exact numeric details are in the methods. PubMed

Neuroplasticity/dendritic architecture (aging & AD models)

• A 2024 study using human iNeurons reported that short peptides—including KED—partially protected against age-related changes (e.g., nuclear morphology, mitochondrial potential) and stimulated dendritogenesis; the authors propose epigenetic/transcriptional mechanisms. Investigational concentrations: low-to-mid micromolar in vitro for 24–72 h. PMC

Pineal immune cells—proliferation vs differentiation

• In rat pineal-derived immune cell cultures, KED did not change differentiation patterns toward T-helper, CTL, or B lineage (unlike Vilon and Epitalon), but increased proliferative potential—a useful negative/positive control indicating context-specific effects across organs. PubMed

Urologic microvascular context (vasculogenic ED)

• A PubMed-indexed Russian clinical paper (English abstract) investigated Vezugen in atherosclerosis-linkedvasculogenic erectile dysfunction; the study sought improvement in microvascular parameters. Methodological granularity is limited in the abstract, but it underscores KED’s vascular positioning. PubMed

Dose ranges tested (illustrative; all investigational)

• Cell culture: KED typically 1–50 µM, 24–72 h, depending on endpoint (proliferation, gene expression). (Ranges inferred from general short-peptide methods; specific KED concentrations should be checked in the original endothelial/iNeuron protocols.)

• Rodent hypoxia: The antihypoxic paper describes peptide injection schedules in rodent models; numeric translation to human dosing is not appropriate (species-specific PK). PubMed

Comparative efficacy/safety (preclinical)

• Efficacy: Signals for endothelial proliferation (Ki-67), stress tolerance, and neuronal dendrite support are consistent across studies, though with varying magnitudes by peptide (e.g., EDR sometimes > KED).

• Safety: No overt toxicity is reported in short-term cell/animal experiments at experimental exposures; one human pilot (2015) reported pro-oxidant chemiluminescence and decreased CD34⁺ cells—an ambiguous finding that requires replication and properly controlled safety evaluation. PubMed

Limitations

• Target validation: Lack of biophysical binding constants and in vivo promoter occupancy metrics for KED; reliance on docking and expression correlations.

• PK/PD: Unknown for KED; difficult to connect dose–exposure–response.

• Replication: Many datasets originate from a limited network; more independent studies are needed.

Human Clinical Evidence

Orientation: Peer-reviewed English-language clinical evidence for Vesugen (KED) is sparse and heterogeneous (small open-label studies, regional trials, non-randomized/observational designs). Where available, we summarize and grade cautiously.

1) Geropreventive pilot (2015): “Cellular and metabolic part of geroprophylactic effects…”

• Design: Open-label cohort; n = 32 (41–83 y) with polymorbidity and organic brain syndrome in remission.

• Interventions: Courses of Pinealon (EDR) and Vesugen (KED) were administered (routes/schedules summarized in the paper’s Russian full text; English abstract does not tabulate exact doses).

• Outcomes: Reported anabolic effect, improved CNS/vital-organ functional indices, and reduction in biological age composites; Vesugen effects were more visible than Pinealon. However, investigators also observed pro-oxidant activity by chemiluminescence and a decrease in CD34⁺ hematopoietic cells—raising safety/PDquestions.

• Evidence grade: C (small, uncontrolled, mixed signals). Investigational dosing used in study: Not establishedfrom English abstract. PubMed

2) Vasculogenic erectile dysfunction (2014): vasoactive tripeptide “Vezugen”

• Design: Clinical study in men with atherosclerotic vasculogenic ED (details limited in English abstract).

• Outcomes: The study was intended to evaluate microvascular/erectile endpoints under tripeptide administration; the abstract supports feasibility but lacks modern randomization/blinding detail.

• Evidence grade: C (limited methodology in abstract). Investigational dosing used in study: Not established from abstract. PubMed

3) Specialty immunology/endocrine observations

• Pineal immune-cell paper (preclinical) is sometimes cited in clinical-adjacent reviews to suggest broader tissue activity; in that system KED increased proliferation but not differentiation—an important nuance that tempers broad claims about immune remodeling. PubMed

Summary of human evidence. At present, robust randomized, placebo-controlled trials of Vesugen with prespecified primary clinical endpoints are not available in indexed English-language literature. Reported pilot benefits (aging composites; urologic vascular function) are hypothesis-generating, while safety ambiguities (e.g., pro-oxidant readouts; CD34⁺ decrease) highlight the need for rigorous, blinded study designs with independent replication. PubMed+1

Comparative Context

Related peptides

• EDR (Pinealon)—neuro-centric tripeptide (Glu–Asp–Arg) with stronger antihypoxic signals in head-to-head rodent work; often studied for neuronal resilience. PubMed

• AEDG (Epitalon)—pineal tetrapeptide with chromatin/telomere literature; appears in aging models and dendritic spine studies.

• KE (Thymogen) or KED (Vilon)—immune/vascular di- and tripeptides used as comparators for differentiationand proliferation effects.

Advantages (research perspective)

• Small size (Mr ≈ 390 g·mol⁻¹) simplifies synthesis and supports high-throughput cell-based screening;

• Promoter-level epigenetic hypothesis offers tractable omics endpoints (MKI67 and other cell-cycle genes);

• Consistent endothelial and dendritic spine signals across complementary models.

Disadvantages/constraints

• PK unknowns make dose-setting and translation difficult;

• Mechanistic granularity is limited (no primary receptor; in vivo DNA binding not proven);

• Human evidence is limited and sometimes ambiguous (mixed PD/safety signals).

Research category placement

Vesugen is best positioned as a vascular-tropic short peptide for bench and preclinical studies on endothelial aging, cell-cycle re-activation, hypoxia stress, and neurovascular crosstalk (e.g., dendrite support under vascular/oxidative stress).

Research Highlights

• Sequence-defined tripeptide (KED), Mr ≈ 390.39 g·mol⁻¹; PubChem 87571363 (free acid). canlabintl.com+1

• Endothelial proliferation: Up-regulates Ki-67 in aged endothelial cultures; docking indicates MKI67 promoterengagement (epigenetic MOA hypothesis). PubMed

• Antihypoxic activity: Protective in hypobaric hypoxia models alongside EDR/AEDG/KE. PubMed

• Neuroplasticity (aging): Supports dendritogenesis/spine maintenance in human induced neurons, extending AD-adjacent spine data. PMC

• Human pilot (aging): Reported improvements in biological age composites but pro-oxidant signals and CD34⁺reduction—highlighting mixed PD and the need for controlled safety/efficacy trials. PubMed

• Urologic microvascular pilot: Vezugen evaluated in vasculogenic ED, consistent with vascular focus; methodology limited. PubMed

Conflicting/uncertain evidence.

• Lack of PK/primary target;

• In vivo promoter occupancy not shown;

• Human outcomes rely on small, uncontrolled or regionally published studies with variable methodology.

Potential Research Applications (no clinical claims; research-use framing)

1. Endothelial aging & cell-cycle re-entry

   • Test KED in senescent human endothelial cells with time-resolved RNA-seq/ATAC-seq, Ki-67/PCNAIHC, and EdU incorporation. Map MKI67 promoter accessibility, H3K27ac, and TF occupancy (e.g., E2F, MYC) with and without KED exposure to verify transcriptional re-activation signatures. PubMed

2. DNA-binding biophysics

   • Undertake surface plasmon resonance, isothermal titration calorimetry, and DNase-I footprinting for MKI67 promoter fragments to quantify KED affinity/specifity; use peptide-ChIP (cross-linkable analog) in cells to test in vivo promoter occupancy—an essential next step beyond docking. PubMed

3. Hypoxia-reperfusion endothelium

   • In H/R models, quantify ROS, Nrf2/ARE activation, mitochondrial membrane potential, and barrier function (TEER) under KED vs controls; compare to EDR/AEDG to define class vs sequence-specificresilience profiles. PubMed

4. Neurovascular crosstalk

   • In organ-on-a-chip microfluidic co-cultures (endothelium + neurons/astrocytes), test KED for dendritepreservation and synaptic gene expression (e.g., CAMK2A, PSD-95) under ischemia-mimetic stress; extend to 5xFAD or Tau organoids for translational relevance. PMC

5. Exploratory human experimental medicine

   • If supported by preclinical PK and safety, design phase-0 studies with circulating endothelial cells, flow-mediated dilation, and oxidative biomarkers as PD readouts; include omics correlates. Any such work would require rigorous randomization, blinding, and independent oversight—currently lacking in the literature base.

Safety & Toxicology

Preclinical/early translational insights

• Cell/rodent work reports no acute toxicity at experimental exposures; however, systematic GLP toxicology (repeat-dose, genotoxicity, reproductive, carcinogenicity) for KED is Not established in indexed English-language literature.

• The human geropreventive pilot noted an increase in chemiluminescent pro-oxidant activity and decrease in CD34⁺ hematopoietic progenitors after peptide courses—an ambiguous finding that warrants dedicated safety studies with controls and longer follow-up. PubMed

Known/theoretical molecular risks

• Unintended proliferation: While endothelial Ki-67 restoration may be beneficial in repair, inappropriate cell-cycle activation could pose theoretical risks (e.g., neointimal growth) without context control—Unknown for KED.

• Off-target DNA interactions: If KED binds DNA/RNA, sequence promiscuity could lead to unintended gene-expression changes—Not established, but an important consideration for epigenetic-style micro-ligands.

Data gaps

• PK (absorption, distribution, metabolism, elimination);

• In vivo target occupancy;

• Dose–exposure–response relationships;

• Multicenter RCT safety with hematologic and oxidative biomarkers prespecified.

Limitations & Controversies

• Evidence base concentration: Many KED studies arise from one research lineage, with limited external replication. PMC

• Mechanistic proof: Docking and expression data support hypotheses, but definitive molecular targets, binding constants, and in vivo occupancy are not yet shown. PubMed

• Clinical translation: The human literature is small, methodologically heterogeneous, and underpowered, with mixed PD signals—progress requires modern RCTs. PubMed

Future Directions

1. Define PK/PD for KED in rodents, then in phase-0 human studies (LC-MS/MS assay development; microdialysis or surrogate exposure biomarkers).

2. Biophysical target validation (DNA/RNA, protein partners) with affinity, specificity, structure–activityrelationships; design KED analogs (D-residues, N-acyl caps) to enhance stability and test on-target vs off-targetprofiles.

3. Mechanistic vascular trials with surrogate PD (e.g., endothelial progenitor counts, FMD, arterial stiffness) and omics endpoints; ensure blinding, randomization, preregistration, and independent analysis.

4. Comparative peptide mapping to delineate KED vs EDR/AEDG/KE in the same platforms (endothelium, neurons, hypoxia).

5. Safety frameworks with hematopoiesis and oxidative panels (e.g., CD34⁺, 8-iso-PGF2α, GSH/GSSG), given the mixed PD seen in the 2015 geropreventive pilot. PubMed

References

1. Khavinson V, et al. Peptide regulation of gene expression: a systematic review. Int J Mol Sci. 2021;22: (PMCID: PMC8619776). (Class-level DNA/RNA interaction framework for short peptides, including KED.) PMC

2. Khavinson V, et al. Epigenetic aspects of peptidergic regulation of vascular endothelium aging. Adv Gerontol.2014;27(3): (PubMed 25051766)—KED increased Ki-67; docking to MKI67 promoter. PubMed

3. Meshchaninov VN, et al. Effect of synthetic peptides on aging and biological age (Pinealon & Vesugen). Adv Gerontol. 2015;28(3): (PubMed 26390612). (Open-label pilot; mixed PD—pro-oxidant signal and ↓CD34⁺.) PubMed

4. Kozina LS, et al. Investigation of antihypoxic properties of short peptides. Ross Fiziol Zh Im I M Sechenova.2008;94(6): (PubMed 18546825). (KED/EDR/AEDG/KE protective in hypobaric hypoxia.) PubMed

5. Kraskovskaya N, et al. Short peptides protect fibroblast-derived induced neurons from aging and stimulate dendritogenesis. Int J Mol Sci. 2024;25:11363. (PMCID: PMC11546785). (Human iNeuron platform; KED among protective peptides.) PMC

6. Linkova NS, et al. Peptidergic stimulation of differentiation of pineal immune cells. Bull Exp Biol Med.2011;151(1): (PubMed 22803057). (KED increased proliferation but not differentiation.) PubMed

7. Kitachev KV, et al. Efficacy of peptide bioregulators in vasculogenic erectile dysfunction. Adv Gerontol.2014;27(1): (PubMed 25051774). (Vasoactive tripeptide “Vezugen”; clinical-adjacent vascular context.) PubMed

Analytical identity/structure references (research-supplier confirmations; not human-use claims):
• CanLab Vesugen entry (sequence KED, formula C₁₅H₂₆N₄O₈, PubChem 87571363). canlabintl.com
• PeptideSciences Vesugen structure listing (same analytical identifiers). Peptide Sciences

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.