Sangamides, a new class of cyclophilin-inhibiting host-targeted antivirals for treatment of HCV infection

Moss, Steven J.; Bobardt, Michael; Leyssen, Pieter; Coates, Nigel; Chatterji, Udayan; Xie, Dong; Foster, Teresa; Liu, Jinlun; Nur‐e‐Alam, Mohammad; Suthar, Dipen; Chen, Yongsheng; Warneck, Tony; Zhang, Ming‐Qiang; Neyts, Johan; Gallay, Philippe; Wilkinson, Barrie; Gregory, Matthew A.

doi:10.1039/c1md00227a

Cited by 25 publications

(32 citation statements)

References 34 publications

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“…This prime discovery was corroborated by subsequent studies, which showed that not only CsA, but non-immunosuppressive CsA derivates such as NIM811, Alisporivir and SCY-635 also block HCV replication [7,13,14,15,16,17]. Moreover, studies showed that sanglifehrins as well as polyketide sanglifehrin derivates also inhibit HCV replication [14,18,19,20]. Sanglifehrins are natural products that also bind Cyps, but are structurally distinct from CsA [19].…”

Section: Resultsmentioning

confidence: 91%

“…CypA possesses a hydrophobic pocket that contains both the enzymatic and ligand binding sites of the protein [29]. CsA, sanglifehrins and their derivates, by binding within this hydrophobic pocket, neutralize both the enzymatic and ligand binding activities of CypA [19,20]. Although CypA has been shown to act as a peptidyl-prolyl cis-trans isomerase in vitro , its true cellular function remains to be demonstrated.…”

Section: Resultsmentioning

confidence: 99%

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Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Hopkins

Gallay

2012

Viruses

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The advent of the replicon system together with advances in cell culture have contributed significantly to our understanding of the function of virally-encoded structural and nonstructural proteins in the replication cycle of the hepatitis C virus. In addition, in vitro systems have been used to identify several host proteins whose expression is critical for supporting such diverse activities as viral entry, RNA replication, particle assembly, and the release of infectious virions. Among all known host proteins that participate in the HCV replication cycle, cyclophilins are unique because they constitute the only host target that has formed the basis of pharmaceutical drug discovery and drug development programs. The introduction of the nonimmunosuppressive cyclophilin inhibitors into clinical testing has confirmed the clinical utility of CsA-based inhibitors for the treatment of individuals with chronic hepatitis C infection and has yielded new insights into their mechanism(s) of action. This review describes the biochemical evidence for the potential roles played by cyclophilins in supporting HCV RNA replication and summarizes clinical trial results obtained with the first generation of nonimmunosuppressive cyclophilin inhibitors.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Hopkins

Gallay

2012

Viruses

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“…5A). We also investigated DY m dissipation by siCK1 under pharmacological inhibition of CypD by treatment with cyclosporin A, sanglifehrin A, and compound BC544 (Moss, 2011). However, none of these CypD inhibitors had any effect on siCK1-induced mitochondrial membrane depolarization (Fig.…”

Section: Depletion Of Ckmt1 Results In Mptmentioning

confidence: 99%

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Datler

Pazarentzos

Mahul‐Mellier

et al. 2014

Journal of Cell Science

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The permeability transition pore (PT-pore) mediates cell death through the dissipation of the mitochondrial membrane potential (DY m ). Because the exact composition of the PT-pore is controversial, it is crucial to investigate the actual molecular constituents and regulators of this complex. We found that mitochondrial creatine kinase-1 (CKMT1) is a universal and functionally necessary gatekeeper of the PT-pore, as its depletion induces mitochondrial depolarization and apoptotic cell death. This can be inhibited efficiently by bongkrekic acid, a compound that is widely used to inhibit the PT-pore. However, when the 'classical' PTpore subunits cyclophilin D and VDAC1 are pharmacologically inhibited or their expression levels reduced, mitochondrial depolarization by CKMT1 depletion remains unaffected. At later stages of drug-induced apoptosis, CKMT1 levels are reduced, suggesting that CKMT1 downregulation acts to reinforce the commitment of cells to apoptosis. A novel high-molecular-mass CKMT1 complex that is distinct from the known CKMT1 octamer disintegrates upon treatment with cytotoxic drugs, concomitant with mitochondrial depolarization. Our study provides evidence that CKMT1 is a key regulator of the PT-pore through a complex that is distinct from the classical PT-pore.

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“…CypI blocks HCV replication by neutralizing the enzymatic activity of CypA. We and others showed that CypA interacts directly with NS5A of multiple genotypes and that this interaction is abrogated by CypI (36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Thus, there is a direct correlation between preventing NS5A-CypA interactions and blocking HCV replication.…”

mentioning

confidence: 80%

Cyclophilin and NS5A Inhibitors, but Not Other Anti-Hepatitis C Virus (HCV) Agents, Preclude HCV-Mediated Formation of Double-Membrane-Vesicle Viral Factories

Chatterji

Bobardt

Tai

et al. 2015

Antimicrob Agents Chemother

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bAlthough the mechanisms of action (MoA) of nonstructural protein 3 inhibitors (NS3i) and NS5B inhibitors (NS5Bi) are well understood, the MoA of cyclophilin inhibitors (CypI) and NS5A inhibitors (NS5Ai) are not fully defined. In this study, we examined whether CypI and NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis of replication complexes (RCs) or with an earlier step of HCV RNA replication, the creation of double-membrane vesicles (DMVs) essential for HCV RNA replication. In contrast to NS5Bi, both CypI and NS5Ai do not block HCV RNA synthesis by way of RCs, suggesting that they exert their antiviral activity prior to the establishment of enzymatically active RCs. We found that viral replication is not a precondition for DMV formation, since the NS3-NS5B polyprotein or NS5A suffices to create DMVs. Importantly, only CypI and NS5Ai, but not NS5Bi, mir-122, or phosphatidylinositol-4 kinase III␣ (PI4KIII␣) inhibitors, prevent NS3-NS5B-mediated DMV formation. NS3-NS5B was unable to create DMVs in cyclophilin A (CypA) knockdown (KD) cells. We also found that the isomerase activity of CypA is absolutely required for DMV formation. This not only suggests that NS5A and CypA act in concert to build membranous viral factories but that CypI and NS5Ai mediate their early anti-HCV effects by preventing the formation of organelles, where HCV replication is normally initiated. This is the first investigation to examine the effect of a large panel of anti-HCV agents on DMV formation, and the results reveal that CypI and NS5Ai act at the same membranous web biogenesis step of HCV RNA replication, thus indicating a new therapeutic target of chronic hepatitis C. Chronic hepatitis C infection affects approximately 200 million people worldwide and is a leading cause of acute and chronic liver diseases (1), and 4 million new hepatitis C virus (HCV) infections occur each year (2, 3). HCV accounts for 2/3 of liver cancer and transplant cases in the developed world (4). Until 2011, the combination of pegylated alpha interferon (IFN-␣) and ribavirin (RBV) had a success rate of ϳ80% in patients with genotypes 2 and 3 but only ϳ50% in patients with genotype 1; most importantly, it causes severe side effects (5-9). There was thus an imperative demand for the identification and development of new anti-HCV agents with diversified mechanisms of action (MoA) in order to deliver interchangeable IFN/RBV-free therapies. Remarkably, new classes of safe and efficacious inhibitors, including direct-acting antiviral (DAAs), such as nonstructural protein 3 inhibitors (NS3i), NS5Ai, and NS5Bi, as well as host-targeting antivirals (HTAs), such as cyclophilin inhibitors (CypI), mir-122 inhibitors (mir-122i), and phosphatidylinositol-4 kinase III␣ inhibitors (PI4KIII␣i), have emerged (10). A number of these compounds have reached IFN-or IFN/RBV-free clinical trials or have been approved. Interestingly, although the mechanisms of action (MoA) of NS3i and NS5Bi are well understood, the MoA of CypI and NS5Ai are not fully defined. In this study...

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Sangamides, a new class of cyclophilin-inhibiting host-targeted antivirals for treatment of HCV infection

Cited by 25 publications

References 34 publications

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Cyclophilin and NS5A Inhibitors, but Not Other Anti-Hepatitis C Virus (HCV) Agents, Preclude HCV-Mediated Formation of Double-Membrane-Vesicle Viral Factories

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