Cyclophilin inhibitor NIM811 ameliorates experimental allergic encephalomyelitis

Huang, Zi Ling; Pandya, Darshan; Banta, Daisy K.; Ansari, Maryam S.; Oh, Unsong

doi:10.1016/j.jneuroim.2017.07.016

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…Cyclophilins are abundant in eukaryotic cells and have important physiologic functions, so questioning their suitability as drug targets is reasonable. Genetic knockouts of individual isoforms A, B, and D in mice are generally well-tolerated, and in fact most studies document positive effects of cyclophilin knockout in disease models (Nigro et al, 2011; Elvers et al, 2012; Guo et al, 2016; Shum et al, 2016; Huang et al, 2017; Wang et al, 2018). More informative than genetic knockouts are the 35 years of clinical experience with CsA and its analogs.…”

Section: Discussionmentioning

confidence: 99%

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

Kuo

Bobardt

Chatterji

et al. 2019

J Pharmacol Exp Ther

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Previous studies show that cyclophilins contribute to many pathologic processes, and cyclophilin inhibitors demonstrate therapeutic activities in many experimental models. However, no drug with cyclophilin inhibition as the primary mode of action has advanced completely through clinical development to market. In this study, we present findings on the cyclophilin inhibitor, CRV431, that highlight its potential as a drug candidate for chronic liver diseases. CRV431 was found to potently inhibit all cyclophilin isoforms tested-A, B, D, and G. Inhibitory constant or IC 50 values ranged from 1 to 7 nM, which was up to 13 times more potent than the parent compound, cyclosporine A (CsA), from which CRV431 was derived. Other CRV431 advantages over CsA as a nontransplant drug candidate were significantly diminished immunosuppressive activity, less drug transporter inhibition, and reduced cytotoxicity potential. Oral dosing to mice and rats led to good blood exposures and a 5-to 15-fold accumulation of CRV431 in liver compared with blood concentrations across a wide range of CRV431 dosing levels. Most importantly, CRV431 decreased liver fibrosis in a 6-week carbon tetrachloride model and in a mouse model of nonalcoholic steatohepatitis (NASH). Additionally, CRV431 administration during a late, oncogenic stage of the NASH disease model resulted in a 50% reduction in the number and size of liver tumors. These findings are consistent with CRV431 targeting fibrosis and cancer through multiple, cyclophilin-mediated mechanisms and support the development of CRV431 as a safe and effective drug candidate for liver diseases. SIGNIFICANCE STATEMENT Cyclophilin inhibitors have demonstrated therapeutic activities in many disease models, but no drug candidates have yet advanced completely through development to market. In this study, CRV431 is shown to potently inhibit multiple cyclophilin isoforms, possess several optimized pharmacological properties, and decrease liver fibrosis and tumors in mouse models of chronic liver disease, which highlights its potential to be the first approved drug primarily targeting cyclophilin isomerases.

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Section: Discussionmentioning

confidence: 99%

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

Kuo

Bobardt

Chatterji

et al. 2019

J Pharmacol Exp Ther

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“…), allergic encephalomyelitis (Huang et al . ), ischaemic‐reperfusion injury after surgical intervention (Garbaisz et al . ), hepatitis C (Arai et al .…”

Section: Introductionmentioning

confidence: 99%

“…A novel CYA derivative, N-methyl-4-isoleucine cyclosporin (NIM811), was found to be highly beneficial in different experimental and clinical studies. NIM811 was effective in animal models of CNS injury (Readnower et al 2011), allergic encephalomyelitis (Huang et al 2017), ischaemic-reperfusion injury after surgical intervention (Garbaisz et al 2014), hepatitis C (Arai et al 2014) liver transplantation (Rehman et al 2011) and pulmonary injury during liver transplantation (Liu et al 2012). Importantly, none of the studies reported side-effects.…”

Section: Introductionmentioning

confidence: 99%

Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Tóth

Maléth

Závogyán

et al. 2019

The Journal of Physiology

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Key points •Bile acids, ethanol and fatty acids affect pancreatic ductal fluid and bicarbonate secretion via mitochondrial damage, ATP depletion and calcium overload. •Pancreatitis‐inducing factors open the membrane transition pore (mPTP) channel via cyclophilin D activation in acinar cells, causing calcium overload and cell death; genetic or pharmacological inhibition of mPTP improves the outcome of acute pancreatitis in animal models. •Here we show that genetic and pharmacological inhibition of mPTP protects mitochondrial homeostasis and cell function evoked by pancreatitis‐inducing factors in pancreatic ductal cells. •The results also show that the novel cyclosporin A derivative NIM811 protects mitochondrial function in acinar and ductal cells, and it preserves bicarbonate transport mechanisms in pancreatic ductal cells. •We found that NIM811 is highly effective in different experimental pancreatitis models and has no side‐effects. NIM811 is a highly suitable compound to be tested in clinical trials. Abstract Mitochondrial dysfunction plays a crucial role in the development of acute pancreatitis (AP); however, no compound is currently available with clinically acceptable effectiveness and safety. In this study, we investigated the effects of a novel mitochondrial transition pore inhibitor, N‐methyl‐4‐isoleucine cyclosporin (NIM811), in AP. Pancreatic ductal and acinar cells were isolated by enzymatic digestion from Bl/6 mice. In vitro measurements were performed by confocal microscopy and microfluorometry. Preventative effects of pharmacological [cylosporin A (2 µm), NIM811 (2 µm)] or genetic (Ppif−/−/Cyp D KO) inhibition of the mitochondrial transition pore (mPTP) during the administration of either bile acids (BA) or ethanol + fatty acids (EtOH+FA) were examined. Toxicity of mPTP inhibition was investigated by detecting apoptosis and necrosis. In vivo effects of the most promising compound, NIM811 (5 or 10 mg kg−1 per os), were checked in three different AP models induced by either caerulein (10 × 50 µg kg−1), EtOH+FA (1.75 g kg−1 ethanol and 750 mg kg−1 palmitic acid) or 4% taurocholic acid (2 ml kg−1). Both genetic and pharmacological inhibition of Cyp D significantly prevented the toxic effects of BA and EtOH+FA by restoring mitochondrial membrane potential (Δψ) and preventing the loss of mitochondrial mass. In vivo experiments revealed that per os administration of NIM811 has a protective effect in AP by reducing oedema, necrosis, leukocyte infiltration and serum amylase level in AP models. Administration of NIM811 had no toxic effects. The novel mitochondrial transition pore inhibitor NIM811 thus seems to be an exceptionally good candidate compound for clinical trials in AP.

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“…Both Debio025 and TRO40303 have been described as useful in experimental models, but due to the clinical failures they did not reached higher levels of clinical trials in AP. Recently, a novel CyA A derivative; N-methyl-4isoleucine cyclosporin (NIM811), was shown to be greatly beneficial in different experimental and clinical studies [14][15][16][17][18][19] . No toxicity or severe or serious adverse effects have been reported in the studies in which NIM811 were used, suggesting that it does not have severe immunosuppressant activity either [20] .…”

Section: Ii1 Targeting the Mitochondrial Transition Pore As Potentimentioning

confidence: 99%

Important therapeutic targets in acute pancreatitis

Tóth

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Cyclophilin inhibitor NIM811 ameliorates experimental allergic encephalomyelitis

Cited by 9 publications

References 33 publications

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

Important therapeutic targets in acute pancreatitis

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