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Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis

Simón Serrano, Sonia LU ; Grönberg, Alvar ; Longato, Lisa ; Rombouts, Krista ; Kuo, Joseph ; Gregory, Matthew ; Moss, Steven ; Elmér, Eskil LU orcid ; Mazza, Giuseppe and Gallay, Philippe , et al. (2019) In Cells 8(11).
Abstract

Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin... (More)

Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Cells
volume
8
issue
11
publisher
MDPI AG
external identifiers
  • scopus:85086910159
  • pmid:31717385
ISSN
2073-4409
DOI
10.3390/cells8111409
language
English
LU publication?
yes
id
3b0d0d50-e82a-4be7-8318-86aa5839d865
date added to LUP
2020-01-13 15:45:11
date last changed
2024-06-26 09:16:01
@article{3b0d0d50-e82a-4be7-8318-86aa5839d865,
  abstract     = {{<p>Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.</p>}},
  author       = {{Simón Serrano, Sonia and Grönberg, Alvar and Longato, Lisa and Rombouts, Krista and Kuo, Joseph and Gregory, Matthew and Moss, Steven and Elmér, Eskil and Mazza, Giuseppe and Gallay, Philippe and Pinzani, Massimo and Hansson, Magnus J and Massoumi, Ramin}},
  issn         = {{2073-4409}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  publisher    = {{MDPI AG}},
  series       = {{Cells}},
  title        = {{Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis}},
  url          = {{http://dx.doi.org/10.3390/cells8111409}},
  doi          = {{10.3390/cells8111409}},
  volume       = {{8}},
  year         = {{2019}},
}