Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-01-23

AUTHORS

Branko Stefanovic, Zarko Manojlovic, Cynthia Vied, Crystal-Dawn Badger, Lela Stefanovic

ABSTRACT

Fibrosis is characterized by excessive production of type I collagen. Biosynthesis of type I collagen in fibrosis is augmented by binding of protein LARP6 to the 5′ stem-loop structure (5′SL), which is found exclusively in type I collagen mRNAs. A high throughput screen was performed to discover inhibitors of LARP6 binding to 5′SL, as potential antifibrotic drugs. The screen yielded one compound (C9) which was able to dissociate LARP6 from 5′ SL RNA in vitro and to inactivate the binding of endogenous LARP6 in cells. Treatment of hepatic stellate cells (liver cells responsible for fibrosis) with nM concentrations of C9 reduced secretion of type I collagen. In precision cut liver slices, as an ex vivo model of hepatic fibrosis, C9 attenuated the profibrotic response at 1 μM. In prophylactic and therapeutic animal models of hepatic fibrosis C9 prevented development of fibrosis or hindered the progression of ongoing fibrosis when administered at 1 mg/kg. Toxicogenetics analysis revealed that only 42 liver genes changed expression after administration of C9 for 4 weeks, suggesting minimal off target effects. Based on these results, C9 represents the first LARP6 inhibitor with significant antifibrotic activity. More... »

PAGES

326

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-36841-y

DOI

http://dx.doi.org/10.1038/s41598-018-36841-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1111634516

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30674965


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