Nidovirusreplikaatiota estää cyklofiliini-inhibiittorit

MIKÄ on solun syklofiliinien idea? Miksi  viruksetkin niitä voivat hyödyntää replikaationsa eduksi? Esim.  CypA  Esimerkki siitä, miten syklofiliini hienosäätää  -   proliinin avaruudellisen asennon muuntamisella -  RNA-replikaatiota   - muokkaamalla viruksen nsp -työkalua.

LÄHDE:

• https://www.ncbi.nlm.nih.gov/pubmed/31315928J Biol Chem. 2019 Aug 30;294(35):13171-13185. doi: 10.1074/jbc.RA119.009537. Epub 2019 Jul 17.  Cyclophilin A allows the allosteric regulation of a structural motif in the disordered domain 2 of NS5A and thereby fine-tunes HCV RNA replication.Dujardin M¹, Madan V², Gandhi NS³, Cantrelle FX¹, Launay H¹, Huvent I¹, Bartenschlager R², Lippens G¹, Hanoulle X⁴. Abstract

• Implicated in numerous human diseases, intrinsically disordered proteins (IDPs) are dynamic ensembles of interconverting conformers that often contain many proline residues. Whether and how proline conformation regulates the functional aspects of IDPs remains an open question, however. Here, we studied the disordered domain 2 of nonstructural protein 5A (NS5A-D2) of hepatitis C virus (HCV). NS5A-D2 comprises a short structural motif (PW-turn) embedded in a proline-rich sequence, whose interaction with the human prolyl isomerase cyclophilin A (CypA) is essential for viral RNA replication. Using NMR, we show here that the PW-turn motif exists in a conformational equilibrium between folded and disordered states. We found that the fraction of conformers in the NS5A-D2 ensemble that adopt the structured motif is allosterically modulated both by the cis/trans isomerization of the surrounding prolines that are CypA substrates and by substitutions conferring resistance to cyclophilin inhibitor. Moreover, we noted that this fraction is directly correlated with HCV RNA replication efficiency. We conclude that CypA can fine-tune the dynamic ensemble of the disordered NS5A-D2, thereby regulating viral RNA replication efficiency.© 2019 Dujardin et al. KEYWORDS:RNA replication; allosteric regulation; conformer ensemble; cyclophilin; hepatitis C virus (HCV); intrinsically disordered protein; nonstructural protein 5A (NS5A); nuclear magnetic resonance (NMR); prolyl isomerase

Ihmisen luomia  syklofiliinin estäjiä:

INHIBIITTORIT

Cyclophilins and cyclophilin inhibitors in nidovirus replication  Author links open overlay panelAdriaan H.de WildeUyenPhamClara C.PosthumaEric J.Snijder

https://doi.org/10.1016/j.virol.2018.06.011Get rights and content

Under a Creative Commons license

https://www.sciencedirect.com/science/article/pii/S0042682218301880

Exem: Cyclophilin D
https://www.ncbi.nlm.nih.gov/pubmed/31474371

Exem:  DeltaCoV
 https://www.ncbi.nlm.nih.gov/pubmed/32090691

(UUSIN pansyklofiliini-inhibiittori:

• Pan-syklofiliini-inhibiittori CRV431

https://www.ncbi.nlm.nih.gov/pubmed/31406003

J Pharmacol Exp Ther. 2019 Nov;371(2):231-241. doi: 10.1124/jpet.119.261099. Epub 2019 Aug 12.

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models.Kuo J¹, Bobardt M¹, Chatterji U¹, Mayo PR¹, Trepanier DJ¹, Foster RT¹, Gallay P², Ure DR².Abstract

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 IC₅₀ 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.
DOI:10.1124/jpet.119.261099

Two major pathologies to which cyclophilins are believed to contribute are fibrosis and cancer. In the liver, fibrosis commonly develops in all the major forms of chronic hepatitis—alcoholic, nonalcoholic, and viral—and is a primary predictor of cirrhosis, hepatocellular carcinoma (HCC), and mortality. Excessive deposition of extracellular matrix can profoundly change the anatomy and physiology of the liver and create an environment that promotes malignancy. HCC is the most common type of primary liver cancer, has a poor prognosis, and annually accounts for approximately 800,000 deaths worldwide (Kulik and El-Serag, 2019). New treatments that positively shift the fibrogenesis–fibrolysis dynamic toward decreasing fibrosis and lowering the risk of HCC are urgently needed.

The most thoroughly characterized chemical class of cyclophilin inhibitors are the cyclosporins. The prototypical inhibitor, CsA, is an 11-amino-acid cyclic peptide that revolutionized solid organ transplantation after its approval as an immunosuppressant in 1983. The mechanism of immunosuppression is binding of CsA to Cyp A, followed by CsA–Cyp A dimer binding to, and inhibition of the lymphocyte-activating phosphatase, calcineurin. Although CsA is a potent inhibitor of cyclophilins, its immunosuppressive activity largely limits its therapeutic use as a cyclophilin inhibitor. To address this limitation, many compounds have been produced that antagonize cyclophilins, but without significant calcineurin inhibition (Sweeney et al., 2014; Dunyak and Gestwicki, 2016). Nonimmunosuppressive analogs of CsA comprise the largest class, and notable representatives are valspodar, NIM811, EDP-546, SCY635, MM284, and alisporivir (DEBIO-025). Alisporivir demonstrated the most clinical potential by advancing through Phase 2 clinical trials with robust antiviral activity toward hepatitis C virus (Buti et al., 2015; Pawlotsky et al., 2015). Cyclophilin inhibitors also have been derived from other chemical platforms—small molecules or derivatives of the macrolide, sanglifehrin A—but they often have shown lower potency than cyclosporin compounds, poor bioavailability, or have not been extensively characterized (Moss et al., 2012; Sweeney et al., 2014; Yan et al., 2015). Despite this diversity of cyclophilin inhibitors, none have advanced completely through clinical development to market.

CRV431 is a CsA analog that is unique from most previously described derivatives, as a result of chemical substitutions made at amino acids 1 and 3 of the cyclosporine ring (Trepanier et al., 2018). Its antiviral activities toward hepatitis B virus, hepatitis C virus, and human immunodeficiency virus-1 and other properties have previously been reported (Gallay et al., 2015, 2019). The present report further documents activities of CRV431 that distinguish it from other members of the cyclosporin class. The data reinforce the potential of pan-cyclophilin inhibitors as safe, therapeutic agents. We show that CRV431 decreases liver fibrosis in two animal models and decreases liver tumor burden in a mouse model of nonalcoholic steatohepatitis (NASH), which highlights its potential as a treatment of liver disease of various etiologies.

• HUOM, Aiemmin  2016  arveltiin jo, että cyklofiliinin estäjistä löytyisi lääkettä  myös koronaviruksia vastaan: (CRV431 on tullut sen jälkeen valoon ja todettu sen teho HBV , HCV, HIV-1, virusinfektioissa. Koronavirusinfektion hoitoon käytöstä  ei ole vielä mainintaa.

• https://www.researchgate.net/publication/309898427_Alisporivir_inhibits_MERS-_and_SARS-coronavirus_replication_in_cell_culture_but_not_SARS-coronavirus_infection_in_a_mouse_model
•  
  Abstract

  Currently, there is no registered treatment for infections with emerging zoonotic coronaviruses like SARS- and MERS-coronavirus. We here report that in cultured cells low-micromolar concentrations of alisporivir, a non-immunosuppressive cyclosporin A-analog, inhibit the replication of four different coronaviruses, including MERS- and SARS-coronavirus. Ribavirin was found to further potentiate the antiviral effect of alisporivir in these cell culture-based infection models, but this combination treatment was unable to improve the outcome of SARS-CoV infection in a mouse model. Nevertheless, our data provide a basis to further explore the potential of Cyp inhibitors as host-directed, broad-spectrum inhibitors of coronavirus replication.