Danegaptide

Summary

Danegaptide is a synthetic dipeptide that modulates connexin‑43 (Cx43) gap‑junction channels and hemichannels. It is being investigated for conditions where Cx43 dysfunction contributes to tissue injury, including acute myocardial infarction, ischemic stroke, cardiac fibrosis, chronic kidney disease, and metabolic disorders affecting adipose tissue.

Mechanism of Action

Danegaptide binds to Cx43 and enhances gap‑junction conductance while inhibiting the opening of Cx43 hemichannels. In cardiac and renal cells it promotes phosphorylation of Cx43 at serine‑368, stabilising the channel at the plasma membrane, reducing ATP release and limiting paracellular leak. By improving intercellular coupling, it can blunt injury‑linked signalling cascades.

What the Research Shows

A phase‑2 randomised trial in STEMI patients gave two intravenous doses of danegaptide during primary PCI; cardiac MRI showed no improvement in myocardial salvage, infarct size, or left‑ventricular function versus placebo. In mouse models of cerebral ischaemia‑reperfusion, danegaptide crossed the blood‑brain barrier, increased astrocytic Cx43 coupling and reduced infarct volume. Chronic administration to Scn5a+/- mice prevented age‑related ventricular fibrosis by preserving Cx43 expression and phosphorylation. In cultured human proximal tubule cells, the peptide blocked TGF‑β1‑induced hemichannel ATP release, restored junctional proteins and lowered pro‑fibrotic cytokine secretion. An adipose‑specific Cx43 over‑expression model showed that combining danegaptide with β3‑adrenergic or FGF21 agonists amplified metabolic responses, suggesting a priming effect on adipocyte gap‑junction networks.

Reported Benefits

Preclinical studies indicate that danegaptide can (1) lessen brain infarct size after stroke, (2) prevent ventricular fibrosis in a genetic mouse model, (3) protect renal tubular cells from TGF‑β1‑mediated injury by blocking harmful hemichannel activity, and (4) improve the efficacy of other metabolic agents in adipose tissue by enhancing gap‑junction coupling. No clinical benefit was demonstrated in the myocardial infarction trial.

Limitations of the Evidence

Human data are limited to a single phase‑2 trial that showed no cardiac benefit, and the trial size was modest. All other positive findings are from animal models or cell cultures, which may not translate to patients. Dosing regimens, long‑term effects, and pharmacokinetics remain incompletely characterised, and the peptide’s ability to reach target tissues in humans is uncertain.

Safety Considerations

The published myocardial infarction study reported no difference in clinical outcomes or adverse events between danegaptide and placebo, but detailed safety data were not provided. Preclinical work did not describe toxicity. Because the compound is still investigational, its safety profile in humans is not established, and caution is warranted pending further trials.

How It Is Administered

In research settings danegaptide has been delivered by intravenous infusion or subcutaneous injection as a hydrochloride peptide formulation. Specific dosing schedules and concentrations vary across studies and are not standardized for clinical use.

Routes of Administration

Goals & Uses

• Prevention of ischemia-reperfusion injuryCardioprotection / CytoprotectionModerate
• Antiarrhythmic effect during reperfusionArrhythmia PreventionLow
• Renal protection in acute kidney injuryRenalModerate
• Cardioprotection after myocardial infarctionCardiovascularModerate
• Reduction of myocardial infarct sizeCardioprotectionModerate
• Improvement of cardiac conductionElectrophysiologyLow

Contraindications

• Known hypersensitivity to Danegaptide or its excipientsAllergyHigh
• Severe pre-existing arrhythmia not related to ischemiaCardiacModerate
• Known hypersensitivity to danegaptide or excipientsAllergyHigh

Adverse Effects

• Injection site reactionsLocalUncommon
• HypotensionCardiovascularUncommonLow blood pressure
• Infusion site erythemaLocalCommon
• NauseaGastrointestinalUncommonFeeling of sickness or urge to vomit
• BradycardiaCardiovascularRare

Drug Interactions

• Concurrent use with other connexin modulatorsModerate
• Antiarrhythmic agents (Class I/III)Moderate
• Thrombolytics / antiplatelet agentsLow

Population Constraints

• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• Pregnant or lactating womenReproductiveRelative
• Pregnant womenReproductiveRelative
• Severe hepatic impairmentOrgan ImpairmentRelative

Regulatory Status

• European UnionInvestigationalClinical trial authorisation only.
• United StatesInvestigationalInvestigational New Drug (IND) status; no approved indication.
• United KingdomInvestigationalSubject to MHRA clinical trial approval.

No FDA or EMA approval; used only within clinical trial protocols.

Evidence & Sources

• Connexin 43 subcellular localization: From trafficking dynamics to pathophysiological outcomes and therapeutic opportunities
  Journal ArticleModerateLi H, et al.2026-01-01T00:00:00.000000Z
• Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial
  Journal ArticleModerateEngstrøm T, et al.2018-01-01T00:00:00.000000Z
• Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice
  Journal ArticleLowFreitas-Andrade M, et al.2020-01-01T00:00:00.000000Z
• Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention
  Journal ArticleLowZhu Y, et al.2022-01-01T00:00:00.000000Z
• Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a(+/)(-) mice
  Journal ArticleLowPatin J, et al.2020-01-01T00:00:00.000000Z
• Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney
  Journal ArticleLowSquires PE, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions