9-(N-methyl-L-isoleucine)-cyclosporin A

Summary

9-(N-methyl-L-isoleucine)-cyclosporin A, also called NIM811, is an investigational cyclic peptide derived from cyclosporin A. It is being studied as a selective inhibitor of mitochondrial cyclophilin D, aiming to prevent the opening of the mitochondrial permeability transition pore. Pre‑clinical work has explored its use in organ transplantation, kidney stone formation, autoimmune neuroinflammation, and acute pancreatitis, where mitochondrial injury is a key driver of tissue damage.

Mechanism of Action

NIM811 binds to cyclophilin D, a mitochondrial matrix protein that regulates the permeability transition pore (mPTP). By blocking cyclophilin D activation, the compound stabilises mitochondrial membrane potential, prevents calcium‑induced pore opening, and reduces the release of pro‑apoptotic factors such as cytochrome c. This action curtails mitochondrial swelling, oxidative stress and downstream cell death pathways, providing cytoprotection in tissues subjected to ischemia‑reperfusion or toxic insults.

What the Research Shows

Pre‑clinical studies demonstrate that NIM811 reduces injury in several models. In a rat liver transplantation model, intravenous NIM811 lowered serum ALT, necrosis, apoptosis and improved graft survival, acting through cyclophilin D interaction to block the mPTP. In rats with ethylene‑glycol‑induced renal calcium crystallisation, oral NIM811 prevented mitochondrial depolarisation, oxidative stress and crystal formation. In mice with experimental allergic encephalomyelitis, NIM811 reduced clinical severity, cytokine expression and CNS infiltrates, implicating both cyclophilin D‑dependent and independent anti‑inflammatory effects. Acute pancreatitis models showed that oral NIM811 (5–10 mg kg⁻¹) protected acinar and ductal cells, preserved bicarbonate transport and reduced oedema, necrosis and serum amylase, with no reported toxicity. Additional in‑vitro work confirms that NIM811, like cyclosporin A, blocks calcium‑triggered, reversible mitochondrial swelling in brain mitochondria. A validated LC‑MS/MS assay has measured NIM811 concentrations in human whole blood, indicating feasibility of pharmacokinetic monitoring.

Reported Benefits

Animal data suggest NIM811 can attenuate mitochondrial‑driven tissue damage, leading to lower enzyme release, reduced cell death and improved functional outcomes in liver grafts, kidney stone models, neuroinflammatory disease, and acute pancreatitis. Its selective cyclophilin D inhibition may offer protection without the broader immunosuppressive effects of cyclosporin A, and pre‑clinical safety signals have been minimal.

Limitations of the Evidence

All efficacy evidence is confined to rodent and in‑vitro studies; no clinical trials have demonstrated benefit in humans. Optimal dosing, formulation and long‑term safety remain undefined. The protective effects may vary by organ and injury type, and some mechanisms (e.g., anti‑inflammatory actions in encephalomyelitis) appear only partially dependent on cyclophilin D. The LC‑MS/MS method confirms exposure but does not establish therapeutic windows.

Safety Considerations

Pre‑clinical reports describe no observable adverse effects of NIM811 at protective doses in rodents, and the compound was well tolerated in acute pancreatitis models. However, human safety data are absent, and potential off‑target effects of cyclophilin inhibition remain unknown. Caution is warranted until formal toxicology and phase‑I studies are completed.

How It Is Administered

NIM811 has been administered intravenously in rat liver transplantation studies and orally in mouse models of pancreatitis and renal crystallisation (5–10 mg kg⁻¹). Formulations used in pre‑clinical work are not detailed, but the compound is soluble enough for both parenteral and oral delivery in animal experiments.

Routes of Administration

Goals & Uses

• HIV-1 replication inhibitionAntiviralLow
• Cytoprotection via mPTP inhibitionCardioprotection / HepatoprotectionLow
• transplant rejection prophylaxisTherapeuticUnknown
• ImmunosuppressionTherapeuticModerate
• autoimmune disease treatmentTherapeuticUnknown
• Hepatitis C virus (HCV) suppressionAntiviralModerate

Contraindications

• Hypersensitivity to cyclosporin or cyclosporin analoguesAllergyHigh
• Severe hepatic impairmentOrganModerateLiver function concerns

Adverse Effects

• HepatotoxicityHepaticUnknownLiver injury or dysfunction
• NeurotoxicityNeurologicalUnknown
• HypertensionCardiovascularUnknownHigh blood pressure
• HeadacheNeurologicUncommonPain in the head or upper neck
• malignancy riskOncologicalUnknown
• Gastrointestinal disturbanceGastrointestinalCommon
• Elevated liver enzymesHepaticUncommonIncrease in AST/ALT or other hepatic markers
• NephrotoxicityRenalUnknown
• Infection susceptibilityImmunologicUnknown

Drug Interactions

• nephrotoxic drugsHigh
• CYP3A4 inhibitors/inducersModerate
• P-glycoprotein substrates/inhibitorsLow
• CYP3A4 inducers (e.g., rifampicin, carbamazepine)Moderate
• P-glycoprotein substratesModerate
• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)Moderate

Population Constraints

• PregnancyReproductive SafetyRelative
• Renal impairmentOrgan ImpairmentRelative
• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric populationAgeRelative
• Severe hepatic impairmentOrgan ImpairmentRelative

Regulatory Status

• European UnionUnapprovedNot in EMA database as approved product
• United StatesInvestigationalOnly used in preclinical and early‑phase clinical studies.
• United KingdomUnknownNo MHRA approval identified

Not listed in FDA Orange Book, EMA database, or major pharmacopeias as of knowledge cutoff. Appears in patent literature (e.g., Novartis cyclosporin analog patents) and research contexts but lacks established clinical development status.

Evidence & Sources

• Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition
  Journal ArticleLowTheruvath TP, et al.2008-01-01T00:00:00.000000Z
• Determination of N-methyl-4-isoleucine-cyclosporin (NIM811) in human whole blood by high performance liquid chromatography-tandem mass spectrometry
  Journal ArticleLowLi W, et al.2007-01-01T00:00:00.000000Z
• Novel effect of the inhibitor of mitochondrial cyclophilin D activation, N-methyl-4-isoleucine cyclosporin, on renal calcium crystallization
  Journal ArticleLowNiimi K, et al.2014-01-01T00:00:00.000000Z
• Calcium-dependent spontaneously reversible remodeling of brain mitochondria
  Journal ArticleLowShalbuyeva N, et al.2006-01-01T00:00:00.000000Z
• Cyclophilin inhibitor NIM811 ameliorates experimental allergic encephalomyelitis
  Journal ArticleLowHuang ZL, et al.2017-01-01T00:00:00.000000Z
• Novel mitochondrial transition pore inhibitor N-methyl-4-isoleucine cyclosporin is a new therapeutic option in acute pancreatitis
  Journal ArticleLowTóth E, et al.2019-01-01T00:00:00.000000Z

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