Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

Fu, Jiping; Tjandra, Meiliana; Becker, Christopher; Bednarczyk, Dallas; Capparelli, Michael; Elling, R.A.; Hanna, Imad; Fujimoto, Roger A.; Furegati, Markus; Karur, Subramanian; Kasprzyk, Theresa; Knapp, Mark; Leung, Kwan; Li, Xin; Lu, Peichao; Mergo, Wosenu; Miault, Charlotte; Ng, Simon; Parker, David; Peng, Yunshan; Roggo, Silvio; Rivkin, Alexey; Simmons, Robert L.; Wang, Michael; Wiedmann, Brigitte; Weiss, Andrew H.; Xiao, Linda; Xie, Lili; Xu, Wei; Yifru, Aregahegn; Yang, Shengtian; Zhou, Bo; Sweeney, Zachary K.

doi:10.1021/jm500862r

Cited by 31 publications

(40 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Still, we cannot exclude Cyps being utilized, which are not blocked or inhibited, to a lesser extent, by the inhibitors. However, it seems more likely that the block of HAV replication by CsA and structurally related compounds is a result of inhibition of ABC transporters such as p‐glycoprotein, which are additional targets of CsA, but most likely not of SFA . Furthermore, the inhibitory effect of Reversan and Piperine, two more specific inhibitors of ABC transporters, supports the concept of a potential role of ABC transporters for HAV‐RNA replication.…”

Section: Discussionmentioning

confidence: 94%

Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication

et al. 2015

View full text Add to dashboard Cite

Hepatitis A virus (HAV) and hepatitis C virus (HCV) are two positive-strand RNA viruses sharing a similar biology, but causing opposing infection outcomes, with HAV always being cleared and HCV establishing persistence in the majority of infections. To gain deeper insight into determinants of replication, persistence, and treatment, we established a homogenous cell-culture model allowing a thorough comparison of RNA replication of both viruses. By screening different human liver-derived cell lines with subgenomic reporter replicons of HAV as well as of different HCV genotypes, we found that Huh7-Lunet cells supported HAV-and HCV-RNA replication with similar efficiency and limited interference between both replicases. HAV and HCV replicons were similarly sensitive to interferon (IFN), but differed in their ability to establish persistent replication in cell culture. In contrast to HCV, HAV replicated independently from microRNA-122 and phosphatidylinositol 4-kinase IIIa and b (PI4KIII). Both viruses were efficiently inhibited by cyclosporin A and NIM811, a nonimmunosuppressive analog thereof, suggesting an overlapping dependency on cyclophilins for replication. However, analysis of a broader set of inhibitors revealed that, in contrast to HCV, HAV does not depend on cyclophilin A, but rather on adenosine-triphosphate-binding cassette transporters and FK506-binding proteins. Finally, silibinin, but not its modified intravenous formulation, efficiently inhibited HAV genome replication in vitro, suggesting oral silibinin as a potential therapeutic option for HAV infections. Conclusion: 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. (HEPATOLOGY 2015;62:397-408) H epatitis C virus (HCV) and hepatitis A virus (HAV) are two hepatotropic positive-strand RNA viruses sharing a similar biology, but causing very different infection outcomes. Worldwide, approximately 160 million people are infected with HCV, a member of the Flaviviridae family. HCV establishes persistence in up to 70%-80% of cases, which often results in severe liver damage. This high rate of persistence is quite unusual for a positive-strand RNA virus, and the underlying reasons are only poorly understood. 1 In contrast, HAV, a picornavirus causing acute self-limited hepatitis, never leads to chronic infection. Counterintuitive to infection outcomes, HCV usually induces a high, long-lasting interferon

show abstract

Section: Discussionmentioning

confidence: 94%

Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Cyclosporine FR901459 was nearly 20-fold more potent than CsA but 4-fold less potent than CsH for inhibiting the FPR1-dependent response [32]. Extensive chemical modification of the cyclosporine scaffold led to the discovery of various non-immunosuppressive cyclophilin inhibitors for the treatment of hepatitis C infection and other diseases [33, 34]. However, the effects of these synthetic cyclosporine analogs on FPR functions have not been reported.…”

Section: Natural Peptides and Their Derivatives As Fpr1 Antagonistsmentioning

confidence: 99%

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

Schepetkin

Khlebnikov

Kirpotina

et al. 2016

International Immunopharmacology

View full text Add to dashboard Cite

Formyl peptide receptor 1 (FPR1) regulates a wide variety of neutrophil functional responses and plays an important role in inflammation and the pathogenesis of various diseases. To date, a variety of natural and synthetic molecules have been identified as FPR1 ligands. Here, we review current knowledge on natural products and natural product-inspired small-molecules reported to antagonize and/or inhibit the FPR1-mediated responses. Based on this literature, additional screening of selected commercially available natural compounds for their ability to inhibit fMLF-induced Ca2+ mobilization in human neutrophils and FPR1 transfected HL-60 cells, and pharmacophore modeling, natural products with potential as FPR1 antagonists are considered and discussed in this review. The identification and characterization of natural products that antagonize FPR1 activity may have potential for the development of novel therapeutics to limit or alter the outcome of inflammatory processes.

show abstract

“…NIM258 -NIM258 (Fig. 8) is a modified cyclosporin analogue that acts as non-immunosuppressive cyclophilin A inhibitor with promising pharmacokinetic profiles against HCV infection (Fu et al, 2014). In comparison to alisporivir, NIM258 decreased transporter inhibition, but maintained comparable efficacy against cyclophilin A (Fu et al, 2014).…”

Section: Immuno-stimulators and Cellular Protein Inhibitorsmentioning

confidence: 99%

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

2017

View full text Add to dashboard Cite

One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.

show abstract

Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

Cited by 31 publications

References 36 publications

Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication

Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

Contact Info

Product

Resources

About