Progress towards discovery of antifibrotic drugs targeting synthesis of type I collagen

Handle URI:
http://hdl.handle.net/10754/564416
Title:
Progress towards discovery of antifibrotic drugs targeting synthesis of type I collagen
Authors:
Fritz, Dillon Jeffery; Cai, Le; Stefanovic, Lela; Stefanovic, Branko
Abstract:
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. © 2011 Bentham Science Publishers Ltd.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Publisher:
Bentham Science Publishers Ltd.
Journal:
Current Medicinal Chemistry
Conference/Event name:
36th International Conference on Micro- and Nano-Engineering (MNE)
Issue Date:
1-Aug-2011
DOI:
10.2174/092986711796504691
PubMed ID:
21728959
Type:
Conference Paper
ISSN:
09298673
Appears in Collections:
Conference Papers; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorFritz, Dillon Jefferyen
dc.contributor.authorCai, Leen
dc.contributor.authorStefanovic, Lelaen
dc.contributor.authorStefanovic, Brankoen
dc.date.accessioned2015-08-04T06:26:53Zen
dc.date.available2015-08-04T06:26:53Zen
dc.date.issued2011-08-01en
dc.identifier.issn09298673en
dc.identifier.pmid21728959en
dc.identifier.doi10.2174/092986711796504691en
dc.identifier.urihttp://hdl.handle.net/10754/564416en
dc.description.abstractType 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. © 2011 Bentham Science Publishers Ltd.en
dc.publisherBentham Science Publishers Ltd.en
dc.subjectDrug screeningen
dc.subjectFibrosisen
dc.subjectFluorescence polarizationen
dc.subjectHigh throughputen
dc.subjectLARP6en
dc.subjectType I collagenen
dc.titleProgress towards discovery of antifibrotic drugs targeting synthesis of type I collagenen
dc.typeConference Paperen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalCurrent Medicinal Chemistryen
dc.conference.date19–22 September 2010en
dc.conference.name36th International Conference on Micro- and Nano-Engineering (MNE)en
dc.conference.locationGenoa, Italyen
dc.contributor.institutionGenScript, INC., 860 Centennial Ave., Piscataway, NJ 08854, United Statesen
dc.contributor.institutionDept. of Biomedical Sciences, College of Medicine, Florida State University, 1115 W Call st, Tallahassee, FL, United Statesen
kaust.authorFritz, Dillon Jefferyen
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