Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold-small molecule interactions
NATURE CHEMISTRY
Authors: Haniff, Hafeez S.; Knerr, Laurent; Liu, Xiaohui; Crynen, Gogce; Bostrom, Jonas; Abegg, Daniel; Adibekian, Alexander; Lekah, Elizabeth; Wang, Kye Won; Cameron, Michael D.; Yildirim, Ilyas; Lemurell, Malin; Disney, Matthew D.
Abstract
A selection-based screen has now revealed preferences in small-molecule chemotypes that bind RNA as well as preferences in the RNA motifs that bind small molecules. Analysis of these data enabled the design of a small molecule that selectively binds a non-coding microRNA and upregulates expression of vascular endothelial growth factor A. 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 repressesVegfamessenger 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.
Role of thalidomide, senicapoc, and sodium butyrate in choroidal neovascularization
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Lyzogubov, Valeriy; Dasso, Michael; Bora, Nalini; Bora, Puran. S.
Abstract
Choroidal neovascularization (CNV) is the hallmark of wet age-related macular degeneration (AMD), a leading cause of irreversible blindness in the modern world. The objective for this study was to investigate the therapeutic potential of known antiangiogenic agents: thalidomide, senicapoc, and sodium butyrate. Dose-dependent effect of the agents on growth of ARPE-19 cells and human umbilical vein endothelial cells (HUVECs) was investigated with cell counting assays. Half-maximal inhibitory concentrations of thalidomide (765 mu M and 1520 mu M), senicapoc (50 mu M and 79 mu M), and sodium butyrate (933 mu M and 557 mu M) were determined for HUVECs and ARPE-19 cells, respectively. Immunofluorescence analysis showed decrease of VEGFA expression in both ARPE-19 cells and HUVECs after treatment only with thalidomide but not with senicapoc or sodium butyrate. Efficacy of the agents was studied in vivo with laser-induced CNV in C57BL/6 mice. Thalidomide (24 mu g), senicapoc (4 mu g), or sodium butyrate (100 mu g) was intravitreally injected the day after CNV induction. Thalidomide, senicapoc, and sodium butyrate inhibited CNV size by 56%, 24%, and 21% respectively on day 7 post-laser. Thalidomide also reduced cobalt chloride induced increase of VEGFA mRNA in ARPE-19 (-33%) and protein in culture medium (-20%). Our results suggest that thalidomide may have more therapeutic potential than senicapoc or sodium butyrate for treatment of CNV or wet AMD. (C) 2020 Elsevier Inc. All rights reserved.
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