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Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions
Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis in human endothelial cells, and increasing its expression is a potential treatment for heart failure. Here, we report the design of a small molecule (TGP-377) that specifically and potently enhances VEGFA expression by the targetin...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571259/ https://www.ncbi.nlm.nih.gov/pubmed/32839603 http://dx.doi.org/10.1038/s41557-020-0514-4 |
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author | Haniff, Hafeez S. Knerr, Laurent Liu, Xiaohui Crynen, Gogce Boström, Jonas Abegg, Daniel Adibekian, Alexander Lekah, Elizabeth Wang, Kye Won Cameron, Michael D. Yildirim, Ilyas Lemurell, Malin Disney, Matthew D. |
author_facet | Haniff, Hafeez S. Knerr, Laurent Liu, Xiaohui Crynen, Gogce Boström, Jonas Abegg, Daniel Adibekian, Alexander Lekah, Elizabeth Wang, Kye Won Cameron, Michael D. Yildirim, Ilyas Lemurell, Malin Disney, Matthew D. |
author_sort | Haniff, Hafeez S. |
collection | PubMed |
description | Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis in human endothelial cells, and increasing its expression is a potential treatment for heart failure. Here, we report the design of a small molecule (TGP-377) that specifically and potently enhances VEGFA expression by the targeting of a non-coding microRNA that regulates its expression. A selection-based screen, named two-dimensional combinatorial screening, revealed preferences in small-molecule chemotypes that bind RNA and preferences in the RNA motifs that bind small molecules. The screening program increased the dataset of known RNA motif–small molecule binding partners by 20-fold. Analysis of this dataset against the RNA-mediated pathways that regulate VEGFA defined that the microRNA-377 precursor, which represses Vegfa messenger RNA translation, is druggable in a selective manner. We designed TGP-377 to potently and specifically upregulate VEGFA in human umbilical vein endothelial cells. These studies illustrate the power of two-dimensional combinatorial screening to define molecular recognition events between ‘undruggable’ biomolecules and small molecules, and the ability of sequence-based design to deliver efficacious structure-specific compounds. |
format | Online Article Text |
id | pubmed-7571259 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-75712592021-02-24 Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions Haniff, Hafeez S. Knerr, Laurent Liu, Xiaohui Crynen, Gogce Boström, Jonas Abegg, Daniel Adibekian, Alexander Lekah, Elizabeth Wang, Kye Won Cameron, Michael D. Yildirim, Ilyas Lemurell, Malin Disney, Matthew D. Nat Chem Article Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis in human endothelial cells, and increasing its expression is a potential treatment for heart failure. Here, we report the design of a small molecule (TGP-377) that specifically and potently enhances VEGFA expression by the targeting of a non-coding microRNA that regulates its expression. A selection-based screen, named two-dimensional combinatorial screening, revealed preferences in small-molecule chemotypes that bind RNA and preferences in the RNA motifs that bind small molecules. The screening program increased the dataset of known RNA motif–small molecule binding partners by 20-fold. Analysis of this dataset against the RNA-mediated pathways that regulate VEGFA defined that the microRNA-377 precursor, which represses Vegfa messenger RNA translation, is druggable in a selective manner. We designed TGP-377 to potently and specifically upregulate VEGFA in human umbilical vein endothelial cells. These studies illustrate the power of two-dimensional combinatorial screening to define molecular recognition events between ‘undruggable’ biomolecules and small molecules, and the ability of sequence-based design to deliver efficacious structure-specific compounds. 2020-08-24 2020-10 /pmc/articles/PMC7571259/ /pubmed/32839603 http://dx.doi.org/10.1038/s41557-020-0514-4 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Haniff, Hafeez S. Knerr, Laurent Liu, Xiaohui Crynen, Gogce Boström, Jonas Abegg, Daniel Adibekian, Alexander Lekah, Elizabeth Wang, Kye Won Cameron, Michael D. Yildirim, Ilyas Lemurell, Malin Disney, Matthew D. Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions |
title | Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions |
title_full | Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions |
title_fullStr | Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions |
title_full_unstemmed | Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions |
title_short | Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions |
title_sort | design of a small molecule that stimulates vascular endothelial growth factor a enabled by screening rna fold–small molecule interactions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571259/ https://www.ncbi.nlm.nih.gov/pubmed/32839603 http://dx.doi.org/10.1038/s41557-020-0514-4 |
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