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Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis

A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening...

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Autores principales: Lee, Chien-Ching, Hung, Chao-Ming, Chen, Chung-Hwan, Hsu, Yi-Chiang, Huang, Yuan-Pin, Huang, Tsung-Bin, Lee, Mon-Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348959/
https://www.ncbi.nlm.nih.gov/pubmed/34361085
http://dx.doi.org/10.3390/ijms22158320
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author Lee, Chien-Ching
Hung, Chao-Ming
Chen, Chung-Hwan
Hsu, Yi-Chiang
Huang, Yuan-Pin
Huang, Tsung-Bin
Lee, Mon-Juan
author_facet Lee, Chien-Ching
Hung, Chao-Ming
Chen, Chung-Hwan
Hsu, Yi-Chiang
Huang, Yuan-Pin
Huang, Tsung-Bin
Lee, Mon-Juan
author_sort Lee, Chien-Ching
collection PubMed
description A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening for potential small-molecule sclerostin inhibitors and to facilitate drug repurposing and drug discovery. Of the 96 selected inhibitors and FDA-approved drugs, six were shown to result in a significant decrease in the fluorescence intensity of the aptamer, suggesting a higher affinity toward sclerostin compared with that of the aptamer. The targets of these potential sclerostin inhibitors were correlated to lipid or bone metabolism, and several of the compounds have already been shown to be potential osteogenic activators, indicating that the aptamer-based competitive drug screening assay offered a potentially reliable strategy for the discovery of target-specific new drugs. The six potential sclerostin inhibitors suppressed the level of both intracellular and/or extracellular sclerostin in mouse osteocyte IDG-SW3 and increased alkaline phosphatase activity in IDG-SW3 cells, human bone marrow-derived mesenchymal stem cells and human fetal osteoblasts hFOB1.19. Potential small-molecule drug candidates obtained in this study are expected to provide new therapeutics for osteoporosis as well as insights into the structure–activity relationship of sclerostin inhibitors for rational drug design.
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spelling pubmed-83489592021-08-08 Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis Lee, Chien-Ching Hung, Chao-Ming Chen, Chung-Hwan Hsu, Yi-Chiang Huang, Yuan-Pin Huang, Tsung-Bin Lee, Mon-Juan Int J Mol Sci Article A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening for potential small-molecule sclerostin inhibitors and to facilitate drug repurposing and drug discovery. Of the 96 selected inhibitors and FDA-approved drugs, six were shown to result in a significant decrease in the fluorescence intensity of the aptamer, suggesting a higher affinity toward sclerostin compared with that of the aptamer. The targets of these potential sclerostin inhibitors were correlated to lipid or bone metabolism, and several of the compounds have already been shown to be potential osteogenic activators, indicating that the aptamer-based competitive drug screening assay offered a potentially reliable strategy for the discovery of target-specific new drugs. The six potential sclerostin inhibitors suppressed the level of both intracellular and/or extracellular sclerostin in mouse osteocyte IDG-SW3 and increased alkaline phosphatase activity in IDG-SW3 cells, human bone marrow-derived mesenchymal stem cells and human fetal osteoblasts hFOB1.19. Potential small-molecule drug candidates obtained in this study are expected to provide new therapeutics for osteoporosis as well as insights into the structure–activity relationship of sclerostin inhibitors for rational drug design. MDPI 2021-08-02 /pmc/articles/PMC8348959/ /pubmed/34361085 http://dx.doi.org/10.3390/ijms22158320 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Chien-Ching
Hung, Chao-Ming
Chen, Chung-Hwan
Hsu, Yi-Chiang
Huang, Yuan-Pin
Huang, Tsung-Bin
Lee, Mon-Juan
Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis
title Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis
title_full Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis
title_fullStr Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis
title_full_unstemmed Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis
title_short Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis
title_sort novel aptamer-based small-molecule drug screening assay to identify potential sclerostin inhibitors against osteoporosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348959/
https://www.ncbi.nlm.nih.gov/pubmed/34361085
http://dx.doi.org/10.3390/ijms22158320
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