Charge-Transfer Interactions Stabilize G-Quadruplex-Forming Thrombin Binding Aptamers and Can Improve Their Anticoagulant Activity

Kévan Pérez de Carvasal (1) , Claudia Riccardi , Irene Russo Krauss , Domenico Cavasso , Jean-Jacques Vasseur (1) , Michael Smietana (1) , François Morvan (1) , Daniela Montesarchio

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

In the search for optimized thrombin binding aptamers (TBAs), we herein describe the synthesis of a library of TBA analogues obtained by end-functionalization with the electron-rich 1,5-dialkoxy naphthalene (DAN) and the electron-deficient 1,8,4,5-naphthalenetetra-carboxylic diimide (NDI) moieties. Indeed, when these G-rich oligonucleotides were folded into the peculiar TBA G-quadruplex (G4) structure, effective donor–acceptor charge transfer interactions between the DAN and NDI residues attached to the extremities of the sequence were induced, providing pseudo-cyclic structures. Alternatively, insertion of NDI groups at both extremities produced TBA analogues stabilized by π–πstacking interactions. All the doubly-modified TBAs were characterized by different biophysical techniques and compared with the analogues carrying only the DAN or NDI residue and unmodified TBA. These modified TBAs exhibited higher nuclease resistance, and their G4 structures were markedly stabilized, as evidenced by increased Tm values compared to TBA. These favorable properties were also associated with improved anticoagulant activity for one DAN/NDI-modified TBA, and for one NDI/NDI-modified TBA. Our results indicated that TBA pseudo-cyclic structuring by ad hoc designed end-functionalization represents an efficient approach to improve the aptamer features, while pre-organizing and stabilizing the G4 structure but allowing sufficient flexibility to the aptamer folding, which is necessary for optimal thrombin recognition.

Mots clés: thrombin binding aptamer; G-quadruplex; 1; 5-dialkoxy naphthalene (DAN); 8; 4; 5naphthalenetetra-carboxylic diimide (NDI); charge transfer; oligonucleotide; anticoagulant activity

Domaines: Chimie analytique; Chimie thérapeutique; Chimie organique; Chimie

Kévan Pérez de Carvasal, Claudia Riccardi, Irene Russo Krauss, Domenico Cavasso, Jean-Jacques Vasseur, et al.. Charge-Transfer Interactions Stabilize G-Quadruplex-Forming Thrombin Binding Aptamers and Can Improve Their Anticoagulant Activity. International Journal of Molecular Sciences, 2021, 22 (17), pp.9510. ⟨10.3390/ijms22179510⟩. ⟨hal-03357457⟩