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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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
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
Descripción
Sumario: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.