Discovery of new G-quadruplex binding chemotypes

Ohnmacht, Stephan A.; Varavipour, Ehsan; Nanjunda, Rupesh; Pazitna, Ingrida; Vita, Gloria Di; Gunaratnam, Mekala; Kumar, Arvind; Ismail, Mohamed A.; Boykin, David W.; Wilson, W. David; Neidle, Stephen

doi:10.1039/c3cc48616h

Cited by 25 publications

(23 citation statements)

References 29 publications

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“…In order to identify small molecules that preferentially stabilise RNA G 4 C 2 G‐Qs, we adapted a FRET‐based G‐Q melting assay (Guyen et al , ; Collie et al , ), to specifically report G 4 C 2 G‐Q stabilisation. We have previously identified several novel G‐Q‐binding chemotypes in the chemical library from the anti‐parasitic drug discovery programme at Georgia State University based on non‐conjugated aromatic diamidines (Ohnmacht et al , ). Here, we screened 138 small molecules, 104 from this library and 34 previously established G‐Q‐binding compounds (Schultes et al , ; Moore et al , ).…”

Section: Resultsmentioning

confidence: 99%

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

Simone¹,

et al. 2017

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Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G‐quadruplex RNA. We investigated their effect in C9orf72 patient iPSC‐derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat‐expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G‐quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G‐quadruplexes has therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

Simone¹,

et al. 2017

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“…In another study, acyclic furan‐ and thiophene‐based compounds 96 – 101 (Figure ) have been identified as putative ligands from 38 representative members of a large chemical library by using a high‐throughput FRET assay against a panel of six G4s and a dsDNA control sequence . Despite the potent G4 stabilizing efficiencies of the six compounds, bis‐phenyl‐monofuran compounds 96 and 97 show slightly better Δ T m values and high selectivity for G4 versus dsDNA.…”

Section: Screening For New Scaffoldsmentioning

confidence: 99%

“…On the other hand, polyfuran compounds 98 and 99 show low antiproliferative activity, even though both seem to be as good G4 ligands as the monofuran compounds. This may be due to cell uptake and nuclear localization problems as well as limited aqueous solubility …”

Section: Screening For New Scaffoldsmentioning

confidence: 99%

Design of Modular G‐quadruplex Ligands

et al. 2018

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Guanine-rich nucleic acid sequences able to form four-stranded structures (G-quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug-like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure-G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.

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“…GQs have found use as a molecular switch (Johnson et al 2013), a biosensor (Wang et al 2011; Zhou et al 2012; Taylor et al 2013), a scaffold for small molecule binding (Rahman et al 2012), and recently as an effector in a high throughput sequencing assay (Chambers et al 2015). There has recently been a flurry of activity on designing and synthesizing GQ binding small molecules due to their potential as anti-cancer drugs (Balasubramanian et al 2011; Husby et al 2013; Iida et al 2013; McLuckie et al 2013; Ohnmacht et al 2014; Neidle 2015). Direct imaging of GQ structures within human cells, both at telomeric and non-telomeric sites, and demonstration of their modulation during the cell cycle have highlighted the significance of protein-GQ interactions (Biffi et al 2013).…”

Section: Introductionmentioning

confidence: 99%

A practical guide to studying G-quadruplex structures using single-molecule FRET

et al. 2017

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In this article, we summarize the knowledge and best practices learned from bulk and single molecule measurements to address some of the frequently experienced difficulties in single molecule Förster Resonance Energy Transfer (smFRET) measurements on G-quadruplex (GQ) structures. The number of studies that use smFRET to investigate the structure, function, dynamics, and interactions of GQ structures has grown significantly in the last few years, with new applications already in sight. However, a number of challenges need to be overcome before reliable and reproducible smFRET data can be obtained in measurements that include GQ. The annealing and storage conditions, the location of fluorophores on the DNA construct, and the ionic conditions of the experiment are some of the factors that are of critical importance for the outcome of measurements, and many of these manifest themselves in unique ways in smFRET assays. By reviewing these aspects and providing a summary of best practices, we aim to provide a practical guide that will help in successfully designing and performing smFRET studies on GQ structures.

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Discovery of new G-quadruplex binding chemotypes

Cited by 25 publications

References 29 publications

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

Design of Modular G‐quadruplex Ligands

A practical guide to studying G-quadruplex structures using single-molecule FRET

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