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Cyclophilin inhibition as potential therapy for liver diseases
Nikolai V. Naoumovemail
Novartis Pharma AG, Basel, Switzerland
Received: February 16, 2014; Received in revised form: July 5, 2014; Accepted: July 7, 2014; Published Online: July 15, 2014
DOI: http://dx.doi.org/10.1016/j.jhep.2014.07.008
http://www.journal-of-hepatology.eu/article/S0168-8278%2814%2900477-2/fulltext
Summary
The cyclophilins are a group of proteins with peptidyl-prolyl isomerase enzymatic activity, localised in different cellular compartments and involved in a variety of functions related to cell metabolism and energy homeostasis, having enhanced expression in inflammation or malignancy. Cyclophilin A (CypA), the most abundantly expressed cyclophilin, is present mainly in the cytoplasm and is a host factor involved in the life cycle of multiple viruses. The extracellular fractions of CypA and CypB are potent pro-inflammatory mediators. CypD, located in mitochondria, is a key regulator of mitochondrial permeability transition pores, and is critical for necrotic cell death. Cyclosporines are the prototype cyclophilin inhibitors. Cyclic peptides, which bind and inhibit cyclophilins without having immunosuppressive properties, have been generated by chemical modifications of cyclosporin A. In addition, cyclophilin inhibitors that are structurally different from cyclosporines have been synthesized. The involvement of cyclophilins in the pathogenesis of different liver diseases has been established using both in vitro and in vivo investigations, thus indicating that cyclophilin inhibition may be of therapeutic benefit. This review summarises the evidence for potential therapeutic applications of non-immunosuppressive cyclophilin inhibitors, alone or in combination with other agents, in virus-induced liver diseases like hepatitis C, B or Delta, liver inflammation and fibrosis, acetaminophen-induced liver toxicity and hepatocellular carcinoma.
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Chronic hepatitis B
The accumulating evidence indicates that cyclophilins are involved in the life cycle of the hepatitis B virus (HBV) in hepatocytes. Early investigations using an HBx protein-dependent model for HBV replication in HepG2 cells, have suggested that changes in mitochondrial calcium flow and blocking cytosolic calcium signalling can impact HBV replication [71]. Cyclophilin inhibition (with either CsA or its non-immunosuppressive derivative NIM811) was shown to interfere with HBV replication by acting on Ca2+ cytosol levels and specifically on the mitochondrial permeability transition pores [71]. More recently, the role of cyclophilins in liver cells, and the effect of cyclophilin inhibitors (NIM811, alisporivir or the sangamide-based cyclophilin inhibitor - NVP018) on HBV replication and HBsAg production were investigated in greater details [[72], [73], [74]]. The involvement of individual cyclophilins was investigated after selective knockdown of CypA, CypC or CypD with specific siRNA [73]. Cyclophilin expression in HuH7 cells was markedly reduced (>80%) after transfection with the corresponding siRNA, which was associated with a significant lowering of HBV-DNA and HBsAg levels. The experiments indicated that CypA is the principal cyclophilin involved in HBsAg production and secretion; incubation with either alisporivir or NIM811 reduced HBV replication and HBsAg levels [[72], [73]]. The effects of cyclophilin inhibition on HBV life cycle were further supported by in vitro and in vivo animal data using a sangamide-based cyclophilin inhibitor - NVP018 [74]. Two-week administration of NPV018 in a mouse HBV model resulted in a 1.2–1.5 log reduction of serum HBV DNA levels along with a decrease in HBsAg titres. HBsAg and CypA are closely associated during secretion from liver cells [75], thus disrupting the CypA/HBsAg complex by cyclophilin inhibitors will be one possible mechanism for reducing the envelope protein secretion.
Collectively, the available data indicate that cyclophilin inhibition with either non-immunosuppressive analogues of CsA or with a sanglifehrin-based inhibitor could be useful in the treatment of patients with chronic hepatitis B, potentially also for hepatitis Delta, as they interfere at multiple sites of the HBV life cycle and HBsAg: first, within the hepatocytes by blocking CypA and CypD, cyclophilin inhibitors will reduce HBV DNA replication as well as HBsAg production/secretion; secondly and independent of the cyclophilin inhibition, by blocking the sodium-taurocholate co-transporter polypeptide (NTCP) on the hepatocyte membrane, recently shown to be a specific receptor for HBV and hepatitis Delta virus [[76], [77], [78]], cyclophilin inhibitors would prevent the entry of these viruses into cells, and infection of new hepatocytes. The potential benefit of combining a cyclophilin inhibitor with some of the well-established HBV antiviral agents will need to be tested in clinical studies to assess whether it will accelerate and/or enhance HBsAg clearance.
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发表于 2014-10-28 18:23
