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Micronutrients in Improvement of the Standard Therapy in Traumatic Brain Injury
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive cyclosporine analog, inhibits the mitochondrial permeability transition pore. Supplementation with NIM811 improved mitochondrial function, cognitive function, and reduced oxidative damage in a severe unilateral controlled cortical impact rat model of TBI.92 Mitochondrial dysfunction can cause increased oxidative damage, loss of respiratory functions, and diminished ability to buffer cytosolic calcium, all of which can cause neuronal death. It was demonstrated that supplementation with U-83836E, a potent inhibitor of lipid peroxyl radicals, reduced both oxidative and nitrosylative damage in cortical homogenates and mitochondria after pTBI in mice model.93
Investigational Antiviral Drugs
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
John Mills, Suzanne M. Crowe, Marianne Martinello
Cyclophilin inhibitors are orally absorbed, nonimmunosuppressive analogs of cyclosporin A, the first “host-targeting” antiviral drugs. Cyclophilin inhibitors block HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant, host-cytosolic protein, cyclophilin A. Because native cyclophilin A is important for HCV NS5A assembly, inhibiting it with a cyclophilin inhibitor blocks HCV replication by blocking NS5A functions. Due to their unique mechanism of antiviral action, cyclophilin inhibitors are pangenotypic, provide a high barrier for development of viral resistance, are active against all common resistance associated substitutions, and demonstrate additive or synergistic effects in vitro with approved DAAs. Cyclophilin inhibitors generally have good pharmacokinetic and safety profiles. Phase I and II clinical studies have demonstrated that cyclophilin inhibitors dramatically reduce viral loads in HCV-infected patients. Phase III studies have been conducted with alisporivir in treatment-naive participants with HCV GT-1, GT-2, and GT-3. In participants with HCV GT-1 (n = 1081), alisporivir (600 mg daily or 400 mg twice daily) was administered in combination with response-guided pegylated interferon and ribavirin (Zeuzem et al., 2015). Overall, SVR12 was 69% in all alisporivir groups compared with 53% in the pegylated interferon and ribavirin control arm. The highest SVR12 (90%) was achieved in participants treated with alisporivir 400 mg twice daily plus pegylated interferon and ribavirin for > 24 weeks. In participants with HCV GT-2 and GT-3 (n = 340), alisporivir (600–1000 mg daily) was administered in combination with ribavirin and/or pegylated interferon. SVR24 (intent to treat [ITT]) in the alisporivir arms ranged from 80% to 85%, compared with 58% in the pegylated interferon plus ribavirin arm. Viral breakthrough occurred, though was infrequent (3%; n = 7 of 258). The most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon alpha and ribavirin were similar to those associated with pegylated interferon alpha and ribavirin used alone. While these interferon-containing strategies will not be used, alisporivir may be explored in combination with interferon-free DAA regimens. Other cyclophilin inhibitors have been administered in proof-of-concept or small exploratory trials, including CPI-431–32, NIM811, and SCY-635. In an in vitro assay using HIV and HCV co-infection, cyclophilin inhibitors, including CPI-431–32, simultaneously inhibits replication of both HCV and HIV-1 when added pre- and postinfection. In 2016, a phase I randomized, double-blind study commenced to assess the safety, pharmacokinetics and efficacy of EDP-494 in healthy volunteers and in treatment-naive subjects with HCV GT-1 and GT-3 (NCT02652377). The future of these “anti-host” drugs is uncertain (Gallay et al., 2013; Gallay et al., 2015; Pawlotsky et al., 2015; Zeuzem et al., 2015).
Mitochondrial dysfunction and mitochondrion-targeted therapeutics in liver diseases
Published in Journal of Drug Targeting, 2021
Li Xiang, Yaru Shao, Yuping Chen
CypD, a peptidyl-prolyl cis-trans isomerase (PPIase) in the mitochondrial matrix, is proved to be an initial factor in the opening of mPTP in response to stress stimuli [116,117] via the Ca2+/p38MAPK/IRE1a/SREBP-1c signalling pathway it participates in TG-buildup and the development of NAFLD [118,119]. Many efforts have been made for CypD inhibitors and NAFLD treatment. Cyclosporin A (CsA), a specific inhibitor of mPTP that lowers the transition of mitochondrial permeability by enhancing the mitochondrial Ca2+ uptake and inhibiting the CypD-PPIase activity [120], was seen to protect hepatocytes by reducing the mitochondrial OS [121]. One derivative of cyclosporin A, N-methyl-4-isoleucine cyclosporin (NIM811), was found to bind to the CypB and thus inhibit HCV replication and could also interact with the CypD to decrease the mitochondrial permeability [122,123]. Besides, NIM811 was strongly antiproliferative to HSCs and greatly reduced collagen production and deposition [124,125]. In addition to enhancing hepatocyte mitophagy, Sirt3 was lately observed to regulate CypD to prevent the opening of mPTP, and thereby suppressed the consequent mitochondrial dysfunction and the progression of NAFLD [126].
Emerging molecular therapeutic targets for spinal cord injury
Published in Expert Opinion on Therapeutic Targets, 2019
Shuo Wang, George M Smith, Michael E. Selzer, Shuxin Li
Repairing damaging mitochondria is potentially important for treating acute SCI and several agents have been employed to maintain mitochondrial function. Immunosuppressant cyclosporin A (CsA) inhibits activation of mitochondrial permeability transition pores in CNS neurons [5] and shows neuroprotection in brain injury and stroke models [3,38], but its therapeutic potential for SCI remains controversial largely due to its high toxicity [39,40]. The less toxic derivative of CsA, NIM811, has neuroprotective effects in animal models of SCI [41]. Treatment with acetyl-L carnitine, a mitochondrial inner membrane component, increases the number of healthy mitochondria and their membrane potential, and alleviates SCI-induced apoptosis in rats [42]. Acetyl-L carnitine provides the acetyl group for synthesizing acetyl-CoA, a necessary chemical in the citric acid cycle. Another compound N-acetylcysteine amide, a variant of glutathione precursor (an FDA-approved drug), when applied immediately after SCI, increases mitochondrial level and functional recovery in SCI rodents [43]. Glutathione is an intracellular thiol compound that protects against damage from ROS, lipid hydroperoxides and electrophiles [44].
Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)
Published in Expert Opinion on Investigational Drugs, 2020
Daren R. Ure, Daniel J. Trepanier, Patrick R. Mayo, Robert T. Foster
Shortly after the discovery of CsA-Cyp A binding, it was found that some synthetic modifications of CsA produced analogs that were largely devoid of immunosuppressive activity but still retained Cyp A binding [28,29]. Several of these nonimmunosuppressive CsA analogs have been made over the past 30 years and have been investigated in many experimental models [30]. The three compounds that have been studied most extensively are NIM811, SCY-635, and alisporivir (Debio-025). All three, and alisporivir most extensively, have been evaluated in in clinical trials for chronic hepatitis C since hepatitis C virus (HCV) replication is dependent on interactions with host cell cyclophilins [31–36]. While largely safe and efficacious, none of the three compounds advanced completely through development for application of regulatory approval. Much has been learned over the years on the structure-activity relationships of CsA analogs, for example on how to minimize drug transporter interactions and how to target the molecules intracellularly and extracellularly [37–40], and compounds continue to be developed and evaluated. CRV431 is one the most recently developed CsA analog and currently in Phase 1 clinical trials. Relevant to liver disease, CRV431 has demonstrated antiviral activity toward hepatitis B and C viruses, anti-fibrotic activity in diet-induced and chemical-induced models of liver fibrosis, and the capacity to decrease NASH-induced liver tumors in mice [41–43]. Other chemical classes also have been explored as cyclophilin inhibitors but generally show disadvantages compared to CsA analogs. For example, the immunosuppressive macrolide, sanglifehrin A, and nonimmunosuppressive sangamide derivatives of it (e.g. NV556), are potent cyclophilin inhibitors but generally have shown poor bioavailability and have not been thoroughly studied, including their toxicology [44–47]. Many types of small molecules also have been made, and some have shown in vivo efficacy, but the cyclophilin inhibition potencies of most of the compounds are lower than those of CsA analogs [48–56]. In similarity to sanglifehrin-derived compounds, no small molecule cyclophilin inhibitors have advanced to clinical trials to our knowledge. Finally, genetic knockdown or knockout technologies have been used extensively to interrogate cyclophilins in experimental models but not yet as clinical therapeutics.