More is not always better: finding the right trade-off between affinity and selectivity of a G-quadruplex ligand

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F18%3A00501728" target="_blank" >RIV/68081707:_____/18:00501728 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1093/nar/gky607" target="_blank" >http://dx.doi.org/10.1093/nar/gky607</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gky607" target="_blank" >10.1093/nar/gky607</a>

Result language

angličtina

Original language name

More is not always better: finding the right trade-off between affinity and selectivity of a G-quadruplex ligand

Original language description

Guanine-rich nucleic acid sequences can fold into four-stranded G-quadruplex (G4) structures. Despite growing evidence for their biological significance, considerable work still needs to be done to detail their cellular occurrence and functions. Herein, we describe an optimized core-extended naphthalene diimide (c(ex)-NDI) to be exploited as a G4 light-up sensor. The sensing mechanism relies on the shift of the aggregate-monomer equilibrium towards the bright monomeric state upon G4 binding. In contrast with the majority of other ligands, this novel c(ex)-NDI is able to discriminate among G4s with different topologies, with a remarkable fluorescent response for the parallel ones. We investigate this sensing by means of biophysical methods, comparing the lead compound to a non-selective analogue. We demonstrate that mitigating the affinity of the binding core for G4s results in an increased selectivity and sensitivity of the fluorescent response. This is achieved by replacing positively charged substituents with diethylene glycol (DEG) side chains. Remarkably, the limit of detection values obtained for parallel G4s are more than one order of magnitude lower than those of the parallel-selective ligand N-methyl mesoporphyrin IX (NMM). Interestingly, the classical fluorescent intercalator displacement (FID) assay failed to reveal binding of c(ex)-NDI to G4 because of the presence a ternary complex (G4-TO-c(ex)-NDI) revealed by electrospray-MS. Our study thus provides a rational basis to design or modify existent scaffolds to redirect the binding preference of G4 ligands.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/EF15_003%2F0000477" target="_blank" >EF15_003/0000477: Structural gymnastics of nucleic acids: from molecular principles through biological functions to therapeutic targets.</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nucleic Acids Research

ISSN

0305-1048

e-ISSN

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Volume of the periodical

46

Issue of the periodical within the volume

19

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

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UT code for WoS article

000450955800004

EID of the result in the Scopus database

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