Selective Binding and Redox-Activity on Parallel G-Quadruplexes by Pegylated Naphthalene Diimide-Copper Complexes

Abstract

G-quadruplexes (G4s) are higher-order supramolecular structures, biologically important in the regulation of many key processes. Among all, the recent discoveries relating to RNA-G4s, including their potential involvement as antiviral targets against COVID-19, have triggered the ever-increasing need to develop selective molecules able to interact with parallel G4s. Naphthalene diimides (NDIs) are widely exploited as G4 ligands, being able to induce and strongly stabilize these structures. Sometimes, a reversible NDI-G4 interaction is also associated with an irreversible one, due to the cleavage and/or modification of G4s by functional-NDIs. This is the case of NDI-Cu-DETA, a copper(II) complex able to cleave G4s in the closest proximity to the target binding site. Herein, we present two original Cu(II)-NDI complexes, inspired by NDI-Cu-DETA, differently functionalized with 2-(2-aminoethoxy)ethanol side-chains, to selectively drive redox-catalyzed activity towards parallel G4s. The selective interaction toward parallel G4 topology, controlled by the presence of 2-(2-aminoethoxy)ethanol side chains, was already firmly demonstrated by us using core-extended NDIs. In the present study, the presence of protonable moieties and the copper(II) cavity, increases the binding affinity and specificity of these two NDIs for a telomeric RNA-G4. Once defined the copper coordination relationship and binding constants by competition titrations, ability in G4 stabilization, and ROS-induced cleavage were analyzed. The propensity in the stabilization of parallel topology was highlighted for both of the new compounds HP2Cu and PE2Cu. The results obtained are particularly promising, paving the way for the development of new selective functional ligands for binding and destructuring parallel G4s.

Effective lowering of α-synuclein expression by targeting G-quadruplex structures within the SNCA gene

“…[38] CD and UV melting experiments in 10 mM lithium cacodylate buffer pH 7.4 and in the presence of 100 mM KCl, showed a melting temperature of 62.4 ± 0.1 °C, as well as FRET-melting analysis revealed a Tm = 68.5 ± 0.6 in the same experimental conditions. These results emphasized that mSNCA is a pretty stable mRNA G4 when compared to other well-known mRNA G4s (TERRA, ADAM10, MMP16) [23,45,46] which melt at around 60°C in the presence of much less potassium chloride (Table S2), following the G-score values identified by bioinformatic analysis. A summary of melting data was reported in Table S4.…”

“…[20,21] Moreover, G4s on 5'-and 3'-UTR mRNAs regions have been correlated with the regulation of the initial stage of the translation process, generally acting as structural silencing factors. [17] Therefore, the selective targeting of G4s, which has been reached successfully by small molecules, [22] is emerging as a novel therapeutic approach for a growing list of different pathologies, such as cancers, [16,18,23] bacterial and viral infections, [24,25] and neurodegenerative diseases. [26] About the last topic, it is important to note that G4s are often recognized as pathogenic drivers in various neurological disorders, with protective or deleterious effects in the cascade of neurotoxic processes.…”

cRGD-Functionalized Silk Fibroin Nanoparticles: A Strategy for Cancer Treatment with a Potent Unselective Naphthalene Diimide Derivative

“…In this way, without its substrate, the enzyme cannot work, and the telomere length can again progressively shorten, ultimately leading to senescence and apoptosis, as with non-malignant cells. Many monomeric and dimeric naphthalene diimide derivatives (NDIs) have been shown to behave according to this mechanism, strongly inducing/stabilizing G-quadruplexes at the telomeric level, thus acting as potent anticancer agents [ 5 , 6 , 7 , 8 , 9 ].…”