Identification of Small Molecule Chemical Inhibitors of the Collagen-Specific Chaperone Hsp47

Thomson, Christy A.; Atkinson, Helen; Ananthanarayanan, Vettai S.

doi:10.1021/jm049148+

Cited by 32 publications

(26 citation statements)

References 31 publications

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“…To date, the administration of antisense oligonucleotides against HSP47 was reported to suppress the accumulation of collagen in experimental glomerulonephritis (31) and peritoneal fibrosis (32). Recently, several low molecular weight compounds were also found to inhibit HSP47 function in vitro (33). In the present study, we found that an HSP47-binding site containing the pairing of a Thr at Yaa Ϫ3 and an Arg at Yaa 0 exhibits the maximum binding to HSP47.…”

Section: Discussionsupporting

confidence: 55%

Specific Recognition of the Collagen Triple Helix by Chaperone HSP47

Koide

Nishikawa

Asada

et al. 2006

Journal of Biological Chemistry

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this finding, we examined the relationship between the structure of Yaa ؊3 and HSP47 binding using synthetic collagenous peptides. The results obtained indicated that the structure of Yaa ؊3 determined the binding affinity for HSP47. Maximal binding was observed when Yaa ؊3 was Thr. Moreover, the required relative spatial arrangement of these key residues in the triple helix was analyzed by taking advantage of heterotrimeric collagen-model peptides, each of which contains one Thr ؊3 and one Arg 0 . The results revealed that HSP47 recognizes the Yaa ؊3 and Arg 0 residues only when they are on the same peptide strand. Taken together, the data obtained led us to define the HSP47-binding structural epitope in the collagen triple helix and also define the HSP47-binding motif in the primary structure. A motif search against human protein database predicted candidate clients for this molecular chaperone. The search result indicated that not all collagen family proteins require the chaperoning by HSP47. Heat-shock protein 47 (HSP47)3 is an essential molecular chaperone for normal procollagen biosynthesis in mammals. Disruption of both alleles of the hsp47 gene in mice causes abnormal procollagen folding in the endoplasmic reticulum (ER), resulting in an embryonic lethal phenotype (1, 2). Although the molecular function of HSP47 remains unclear, it has been suggested that HSP47 could stabilize correctly folded triple-helical intermediates of procollagen that are otherwise unstable at body temperature (3, 4). HSP47 has also been suggested to inhibit lateral associations that form insoluble aggregates in the ER (5). Efforts toward elucidating the collagen-recognition mechanism of HSP47 have been made by our group and others, and to date, Arg residues at Yaa positions in the collagenous Gly-Xaa-Yaa repeats have been shown to be necessary for interaction with HSP47 (6, 7). The importance of the triple-helical structure for HSP47 binding has also been strongly suggested, and it was finally proven in the preceding paper by using conformationally constrained collagenous peptides (8). The minimal number of Arg residues per triple helix required for the specific interaction was further determined to be one. In addition, the Yaa residue occupying position Ϫ3 (denoted as Yaa Ϫ3 , and similar nomenclatures are used later), based on the essential Arg residue at a Yaa position (whose position is defined as position 0), has also been suggested to be important for the interaction, since replacement of the 4-hydoxy-Lproline (Hyp) residue at position Ϫ3 in (Pro-Hyp-Gly) 2 -Pro-Hyp Ϫ3 -Gly-Pro-Arg 0 -Gly-(Pro-Hyp-Gly) 4 -Pro-Hyp-amide with p-benzoyl-Lphenylalanine (Bpa) abolished the binding, even though the peptide had a triple-helical structure and contained an Arg residue at a Yaa position.In the present study, we focused on the structure of Yaa Ϫ3 , which was expected to be another structural determinant for HSP47 binding, together with the side chain structure of Arg 0 . A structure-activity relationship study was performed using coll...

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Section: Discussionsupporting

confidence: 55%

Specific Recognition of the Collagen Triple Helix by Chaperone HSP47

Koide

Nishikawa

Asada

et al. 2006

Journal of Biological Chemistry

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“…Our study indicates that coding mutations of the SERPINH1 gene might be responsible for recessive forms of human OI, where no mutation in the four known OI genes has been found. It has been proposed to develop SERPINH1 binding molecules as drugs against fibrosis [23]. The findings of our study emphasize that such a therapeutic strategy will have to be very carefully adjusted in order not to have adverse effects on the physiological production of collagen.…”

Section: Discussionmentioning

confidence: 92%

A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta

et al. 2009

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Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.

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“…Chemical inhibitors of HSP47 have been previously developed, as lead compounds potentially useful for controlling fibrosis and metastasis [44]. Therefore, in light of the above results, we wondered whether the levels of Aβ peptides in the conditioned medium could be inhibited not only by decreasing HSP47 levels, but also by modulating its biochemical activity.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, in light of the above results, we wondered whether the levels of Aβ peptides in the conditioned medium could be inhibited not only by decreasing HSP47 levels, but also by modulating its biochemical activity. To address this point, we treated APPsw cells with three previously described HSP47 inhibitors [44], which are capable to affect its collagen-folding ability at low-micromolar concentrations. The HSP47 inhibitors had no detrimental effects on cell viability at concentrations as high as 100 µM (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Since the HSP47 inhibitors act most likely by non-covalent binding [44] we reasoned that, if these effects were specific, they should be overcome by increasing HSP47 levels. Therefore, we measured the amount of Aβ peptides in the conditioned medium of 293sw cells transfected with an HSP47 expression construct or with a control vector, after treatment with vehicle only or with the Compound IV (7.5 µM).…”

Section: Resultsmentioning

confidence: 99%

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The Collagen Chaperone HSP47 Is a New Interactor of APP that Affects the Levels of Extracellular Beta-Amyloid Peptides

et al. 2011

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Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Aβ peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Aβ peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques.

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Identification of Small Molecule Chemical Inhibitors of the Collagen-Specific Chaperone Hsp47

Cited by 32 publications

References 31 publications

Specific Recognition of the Collagen Triple Helix by Chaperone HSP47

Specific Recognition of the Collagen Triple Helix by Chaperone HSP47

A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta

The Collagen Chaperone HSP47 Is a New Interactor of APP that Affects the Levels of Extracellular Beta-Amyloid Peptides

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