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Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound

Title: Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound : antifibrotic drug.
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Name(s): Stefanovic, Branko, author
Manojlovic, Zarko, author
Vied, Cynthia, author
Badger, Crystal-Dawn, author
Stefanovic, Lela, author
Type of Resource: text
Genre: Text
Journal Article
Date Issued: 2019/01/23
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_libsubv1_scholarship_submission_1550162176_d38b7a2e (IID), 10.1038/s41598-018-36841-y (DOI)
Keywords: fibrosis, therapy, drug screening
Publication Note: The version of record can be found at https://www.doi.org/10.1038/s41598-018-36841-y.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1550162176_d38b7a2e
Owner Institution: FSU
Is Part Of: Scientific Reports.
Issue: iss. 9(1), vol. 23

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Stefanovic, B., Manojlovic, Z., Vied, C., Badger, C. -D., & Stefanovic, L. (2019). Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound : antifibrotic drug. Scientific Reports. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1550162176_d38b7a2e