SDZ 811 / Novartis - LARVOL DELTA

CypA inhibition attenuates diabetic hypoglycemia-induced cognitive impairment via the CD147/NF-κB/MMP-9 pathway. (PubMed, Biochem Pharmacol) - "Cyclosporin A (CsA) was used as a pharmacological cyclophilin inhibitor, and orthogonal pharmacological controls (FK506 and NIM811) were included to assess specificity in vitro. Collectively, our findings identify the CypA-mediated CD147/NF-κB/MMP-9 inflammatory pathway as a key mechanism driving hypoglycemia-induced cognitive dysfunction in diabetes via pericyte injury and BBB disruption. These data support pharmacological cyclophilin/CypA inhibition as a promising strategy for neurovascular protection and cognitive improvement."

Journal • Alzheimer's Disease • Cognitive Disorders • Diabetes • Hypoglycemia • Metabolic Disorders • BSG • MMP9

Targeting DNA fragment extrusion: a new therapeutic avenue for CCl4-induced hepatic injury. (PubMed, Mol Biol Rep) - No abstract available

Journal • Hepatology • Liver Failure

Broad-Spectrum Antiviral Activity of Cyclophilin Inhibitors Against Coronaviruses: A Systematic Review. (PubMed, Int J Mol Sci) - "In this systematic review, we examined cell culture, animal model, and clinical studies assessing the anti-viral efficacy of cyclosporine A (CsA, PubChem CID: 5284373) and its non-immunosuppressive derivatives against coronaviruses...Non-immunosuppressive analogs such as Alisporivir and NIM811 exhibited similar inhibitory effects...Mechanistic studies revealed that CsA disrupts the formation of viral replication complexes, interferes with critical Cyp-viral protein interactions, and modulates innate immune signaling. These findings collectively demonstrate the therapeutic potential of cyclophilin inhibitors as broad-spectrum anti-virals against current and emerging coronaviruses."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Mechanisms Underlying Cyclosporine A-Mediated Promotion of HEV Replication (APASL 2025) - "Background: Hepatitis E virus (HEV) infection is an acute, self-limiting disease. Our study demonstrates that CsA and its derivative NIM811 promote HEV replication by inhibiting the expression of their intracellular targets, CypA and CypB. Furthermore, we elucidate that this process is associated with increased HEV RNA stability. SAMHD1 plays a critical role in RNA degradation."

Hepatology • Infectious Disease • Inflammation • RACK1

Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury. (PubMed, Liver Res) - "Premedication with CsA or NIM-811 mitigated hepatic IRI in mice, as evidenced by the decreased ALT and reduced injury on histology. These results have potential implications on mitigating IRI during liver transplantation and resection."

Journal • Preclinical • Cardiovascular • Hepatology • Liver Failure • Metabolic Disorders • Oncology • Reperfusion Injury • Transplantation • IL10 • IL2 • IL4

Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies. (PubMed, Protein Sci) - "Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response."

Journal • Infectious Disease

Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors. (PubMed, Commun Biol) - "In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies oxidative phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo...Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate."

Journal • Hematological Disorders • PPIF

Manipulation of cyclophilin D and mitochondrial permeability transition pore to alter neonatal cardiac function and regeneration. (PAS 2024) - "Deletion or inhibition (cyclosporin A, NIM811) of CypD or activation of the PTP (BZ-423) can affect cardiomyocyte proliferation and function. For other analyses, we will analyze at least 5 independent replicates. Data will be analyzed for I) the presence of time effects, which differ by treatment group; ll) the presence of time effects but no difference between treatment groups; lll) treatment group differences, independent of time."

Fibrosis • Immunology • PPIF

TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6. (PubMed, Nature) - "Second, cyclophilin A (CypA) is recruited via interaction with the capsid protein L3 to virus factories and virions to antagonize TRIM5α; this interaction is prevented by cyclosporine A (CsA) and the non-immunosuppressive derivatives alisporivir and NIM811. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses, and because these drugs target a cellular protein, CypA, the emergence of viral drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses, including monkeypox and variola."

Journal • Human Immunodeficiency Virus • Infectious Disease • TRIM5

SARS-COV-2 viroporins activate the NLRP3-inflammasome by the mitochondrial permeability transition pore. (PubMed, Front Immunol) - "Our findings revealed that mROS activates the release of mitochondrial DNA via the NIM811-sensitive mitochondrial-permeability-pore(mtPTP), activating the inflammasome. Hence, interventions targeting mROS and the mtPTP may mitigate the severity of COVID-19 cytokine storms."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • GLI2 • IL1B • NLRP3

The Novel Cyclophilin D Inhibitor CC-2055 Exerts Anti-Seizure Effects in the Mouse Pilocarpine Model of Epilepsy Via Rescue of Hippocampal Parvalbumin-Positive Interneurons (AES 2022) - "Earlier, we reported that pharmacological inhibition of CypD with cyclosporin A or N-methyl-4-isoleucine-cyclosporin (NIM811) renders anti-seizure effects in epileptic Kcna1-null mice (PMID: 25899847). The novel CypD antagonist, CC-2055, induces anti-seizure effects in the mouse pilocarpine model of epilepsy. CC-2055 also appears to restore PV+ interneuron numbers in CA1 hippocampus and reverses the electrophysiological changes in CA1 pyramidal cells from pilocarpine-treated mice. Taken together, our preliminary results further support the scientific rationale for the development of CypD antagonists as novel anti-seizure medications."

Late-breaking abstract • Preclinical • CNS Disorders • Epilepsy • PPIF

The Role and Mechanism of Cyclophilin A in Cisplatin-Induced AKI (KIDNEY WEEK 2022) - "Cyclophilin A (CypA) is an intracellular receptor for the immunosuppressant cyclosporin A (CsA), and is reported to function in protein folding, signal transduction, inflammation, tumorigenesis and viral replication, while the specific role of CypA in CP-induced AKI still lacks in-depth research. Methods Here, we successfully established an AKI mice model via a single intraperitoneal injection of CP (25mg/kg), and a CsA derivative, NIM811, was used as an inhibitor of CpyA to treat the CP mice...Conclusion CypA is increased and plays an injurious role in CP-induced AKI. And the underlying mechanism may attribute to promoting apoptosis by dysregulated CD147 and AKT/AMPK/mTOR signaling pathways."

Acute Kidney Injury • Immunology • Inflammation • Nephrology • Oncology • Renal Disease • BSG • CASP3

Mitochondrial Permeability Transition in Stem Cells, Development, and Disease. (PubMed, Adv Exp Med Biol) - "Future studies should clarify ambiguities in mPTP structure and reveal new roles for mPT in dictating specialized cellular functions beyond cell survival that are tied to mitochondrial fitness including stem cell self-renewal and fate. The focus of this review is to describe contemporary models of the mPTP and highlight how pore activity impacts stem cells and development."

Journal • Developmental Disorders • PPIF

The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia-reperfusion in vivo. (PubMed, Sci Rep) - "These findings are clinically relevant as MCP-1, IL-23, IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after ischemia-reperfusion injury."

Journal • Preclinical • Hepatology • Liver Failure • Reperfusion Injury • IL1A • IL6

Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology. (PubMed, Cells) - "CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI."

Journal • CNS Disorders • Metabolic Disorders • Vascular Neurology • PPIF

[VIRTUAL] Modulation of the Tumor Suppressor Protein PP2A Using a Small Molecule Agonist Overcomes Multi-Drug Resistance through Mitochondrial Permeability Transition Pore (MPTP) Dependent Induction of Apoptosis in Chronic Lymphocytic Leukemia (ASH 2020) - "Venetoclax (VEN, an inhibitor of Bcl-2) and ibrutinib (IBR, an inhibitor of BTK) generated excellent clinical responses in CLL patients singly and even more effectively in combination (Portell et al...Additionally, our analysis using the CalceinAM/CoCl2 method revealed that DT061 was able to induce MPTP opening in primary CLL cells, which was inhibited in the presence of NIM811 or CspA, suggesting that DT061 induces apoptosis through MPTP activation (Fig...The apoptosis induction was dependent on MPTP activation. Collectively, this work highlights the existence of an anti-apoptotic multi-drug resistant pool of CLL cells in patients, and validates a novel pharmaceutically tractable pathway to deplete this reservoir."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1 • CD40LG • IL10 • NFKB1

Suppression of NLRP3 Inflammasome, Pyroptosis, and Cell Death by NIM811 in Rotenone-Exposed Cells as an in vitro Model of Parkinson's Disease. (PubMed, Neurodegener Dis) - "These results provide evidence that rotenone activates the NLRP3 inflammomere and induces pyroptosis. NIM811 protects the cell from rotenone-induced damage and inhibits NLRP3 inflammasome and pyroptosis. NIM811 might serve as a potential therapeutic drug in the treatment of PD."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] The Effects of Novel Cyclophilin D Inhibitors on Mitochondrial Permeability Transition Pore Opening (AES 2020) - "We have previously shown that pharmacological inhibition of CypD with cyclosporin A (CsA) or N-methyl-4-isoleucine-cyclosporin (NIM811) renders anti-seizure effects in epileptic Kcna1-null mice (PMID: 25899847). Both CC-2205 and CC-4126 (at 1 µM) inhibit Ca2+-mediated MPTP opening via CypD binding with similar effectiveness. These novel compounds may represent potential therapies for a broad array of conditions associated with mitochondrial dysfunction and neurodegeneration. Funding: University of Calgary, Alberta Children’s Hospital Research Institute"

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Epilepsy • Genetic Disorders • Huntington's Disease • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Vascular Neurology • PPIF

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases. (PubMed, iScience) - "Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • JAK2

Interaction of cyclophilin a and human coronavirus 229E N protein is essential for virus replication. (PubMed, Antiviral Res) - "We further show the inhibitory potential of non-immunosuppressive CsA derivatives Alisporivir, NIM811, compound 3 on HCoV-229E-GFP and -Luciferase replication in human Huh-7.5 hepatoma cells at 18 and 48 h time points post infection with EC s at low micromolar ranges. Thus, non-immunosuppressive CsA derivatives effectively inhibit HCoV-229E replication suggesting them as possible candidates for the treatment of HCoV infection. The interruption of interaction between CypA and N protein by CsA and its derivatives suggest a mechanism how CypA inhibitors suppress viral replication."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Infectious Disease • Novel Coronavirus Disease • Solid Tumor

Novel mitochondrial transition pore inhibitor N-methyl-4-isoleucine cyclosporin is a new therapeutic option in acute pancreatitis. (PubMed, J Physiol) - "•Bile acids, ethanol and fatty acids deteriorate pancreatic ductal fluid and bicarbonate secretion via mitochondrial damage, ATP depletion and calcium overload. •It is known that pancreatitis inducing factors open the membrane transition pore (mPTP) channel via cyclophilin D activation in acinar cells causing calcium overload and cell death and genetic or pharmacological inhibition of mPTP improves the outcome of acute pancreatitis in animal models. •In our study we show that genetic and pharmacological inhibition of mPTP protects mitochondrial homeostasis and cell function evoked by pancreatitis-inducing factors in pancreatic ductal cells. •Our results also reveal that the novel Cyclosporin A derivative NIM811 protects mitochondrial function in acinar and ductal cells, moreover it preserves bicarbonate transport mechanisms in pancreatic ductal cells. •We found that NIM811 is highly effective in different experimental pancreatitis models and that NIM811 has no..."

Journal • Pancreatitis

Novel perspectives for Hepatitis A Virus therapy revealed by comparative analysis of Hepatitis C Virus and Hepatitis A Virus RNA replication. (PubMed) - "We established a cell culture model enabling comparative studies on RNA replication of HAV and HCV in a homogenous cellular background with comparable replication efficiency. We thereby identified new host cell targets and potential treatment options for HAV and set the ground for future studies to unravel determinants of clearance and persistence."

Journal • Biosimilar • Hepatitis C Virus • Immunology • Inflammation

Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury. (PubMed, Neural Regen Res) - "One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition (mPT) state due to formation of the cyclosporine A sensitive permeability transition pore (mPTP). In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex-perimental strategies targeting the mPTP."

Journal • Review • Biosimilar • Brain Cancer • Complement-mediated Rare Disorders

Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme. (PubMed) - Cell Death Dis - "On the other hand, mTOR inhibitors rescued cells from NIM811-induced paraptosis by sustaining autophagy and the UPR, while specifically restraining cap-dependent translation. These findings not only provide new insights into the mechanisms underlying paraptosis, but also shed light on a potential approach to enhance GBM treatment."

Journal • Biosimilar • Oncology

Inhibition of the mitochondrial permeability transition improves bone fracture repair. (PubMed, Bone) - "Using a bone fracture model in mice, we observed that bone formation and biomechanical properties of repaired bones were significantly increased in CypD knock-out mice or wild type mice treated with a CypD inhibitor, NIM811, when compared to controls...In contrast to global CypD knock-out, mesenchymal lineage-specific (Prx1-Cre driven) CypD deletion did not result in improved fracture repair. Our findings implicate MPTP in bone fracture and suggest systemic CypD inhibition as a modality to promote fracture repair."

Journal