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Progress Towards Discovery of Antifibrotic Drugs Targeting Synthesis of Type I Collagen.
MedLine Citation:
PMID:  21728959     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Type I collagen is the most abundant protein in human body. Fibrosis is characterized by excessive synthesis of type I collagen in parenchymal organs. It is a leading cause of morbidity and mortality worldwide, about 45% of all natural deaths are attributable to some fibroproliferative disease. There is no cure for fibrosis. To find specific antifibrotic therapy targeting type I collagen, critical molecular interactions regulating its synthesis must be elucidated. Type I and type III collagen mRNAs have a unique sequence element at the 5' end, the 5' stem-loop. This stem-loop is not found in any other mRNA. We cloned LARP6 as the protein which binds collagen 5' stem-loop with high affinity and specificity. Mutation of the 5' stem-loop or knock down of LARP6 greatly diminishes collagen expression. Mice with mutation of the 5' stem-loop are resistant to development of liver fibrosis. LARP6 associates collagen mRNAs with filaments composed of nonmuscle myosin; disruption of these filaments abolishes synthesis of type I collagen. Thus, LARP6 dependent collagen synthesis is the specific mechanism of high collagen expression seen in fibrosis. We developed fluorescence polarization (FP) method to screen for drugs that can inhibit binding of LARP6 to 5' stem-loop RNA. FP is high when LARP6 is bound, but decreases to low levels when the binding is competed out. Thus, by measuring decrease in FP it is possible to identify chemical compounds that can dissociate LARP6 from the 5' stem-loop. The method is simple, fast and suitable for high throughput screening.
Authors:
D Fritz; L Cai; L Stefanovic; B Stefanovic
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-4
Journal Detail:
Title:  Current medicinal chemistry     Volume:  -     ISSN:  1875-533X     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-6     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9440157     Medline TA:  Curr Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Biomedical Sciences, College of Medicine, Florida State University, 1115, West Call Street, Tallahassee, FL 32306, USA. branko.stefanovic@med.fsu.edu.
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