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Cells. 2019 Nov 8;8(11). pii: E1409. doi: 10.3390/cells8111409.

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

Author information

1
Department of Laboratory Medicine, Translational Cancer Research, Lund University, Medicon Village, 223 63 Lund, Sweden.
2
NeuroVive Pharmaceutical AB, 223 63 Lund, Sweden.
3
Engitix Ltd., London NW3 2PF, UK.
4
Regenerative Medicine & Fibrosis Group, Institute for Liver & Digestive Health, University College London, Royal Free Hospital, London NW3 2PF, UK.
5
Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
6
Isomerase Therapeutics Ltd., Cambridge CB10 1XL, UK.
7
Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, 221 84 Lund, Sweden.

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 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.

KEYWORDS:

3D in vitro model; NV556; STAM; cyclophilin; decellularized human liver; hepatic stellate cells (HSC); liver fibrosis; methionine-choline-deficient (MCD) diet; nonalcoholic steatohepatitis

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