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

2021 ◽  
Vol 22 (17) ◽  
pp. 9510
Author(s):  
Kévan Pérez de Carvasal ◽  
Claudia Riccardi ◽  
Irene Russo Krauss ◽  
Domenico Cavasso ◽  
Jean-Jacques Vasseur ◽  
...  
Keyword(s):  
Charge Transfer ◽  
Ad Hoc ◽  
Anticoagulant Activity ◽  
Stacking Interactions ◽  
Efficient Approach ◽  
Π Stacking ◽  
G Quadruplex ◽  
Nuclease Resistance ◽  
Donor Acceptor ◽  
Biophysical Techniques

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–π stacking 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.

Exploiting hydrogen bonding interactions to probe smaller linear and cyclic diamines binding to G-quadruplexes: a DFT and molecular dynamics study

2017 ◽  
Vol 19 (18) ◽  
pp. 11474-11484 ◽  
Author(s):  
Mrinal Kanti Si ◽  
Anik Sen ◽  
Bishwajit Ganguly
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonding ◽  
Binding Motif ◽  
Stacking Interactions ◽  
Hydrogen Bonding Interactions ◽  
Π Stacking ◽  
G Quadruplex

This report reveals that hydrogen bonding interactions between the ligand and G-quadruplex can initiate an alternative binding motif to typical π-stacking interactions.

Interaction of manganese corroles with TCNQ and related acceptor molecules

2020 ◽  
Vol 24 (05n07) ◽  
pp. 705-711
Author(s):  
Benedikt Wolfram ◽  
Çağla Baş ◽  
Christian Kleeberg ◽  
Martin Bröring
Keyword(s):  
Charge Transfer ◽  
Single Crystals ◽  
High Reactivity ◽  
Geometric Parameters ◽  
Oxidation States ◽  
Stacking Interactions ◽  
Oxygenated Compounds ◽  
Axial Ligands ◽  
Donor Acceptor ◽  
New Compounds

Manganese corroles with the Mn atom in the oxidation states +III and +IV have been probed as donor moieties for supramolecular stacked donor–acceptor complexes with the typical acceptor units TCNQ (tetracyanoquinone), TCNP (tetracyanopyrazine), and TCNB (tetracyanobenzene). Four new compounds formed as single crystals from different co-crystallization attempts. In those cases where a Mn(III) corrole was used as the donor component, hydrolyzed and/or oxygenated compounds [(cor)Mn(TCNQ*)] and [(cor*)Mn(TCNP*)] were obtained as the exclusive products. With chloridomanganese(IV) corroles, sandwich-like 2:1 complexes [(cor)MnCl][Formula: see text][TCNQ] and [(cor)MnCl][Formula: see text][TCNB] form, with both components left intact. Crystallographic analyses reveal partial or complete charge transfer to unusual axial ligands and thus prove the high reactivity of Mn(III) corroles in the first two cases. For the sandwich arrangements, almost-unaltered geometric parameters of the Mn(IV) corroles are observed, pointing to negligible structural consequences for metal corroles when engaged in stacking interactions.

A self-repairing, supramolecular polymer system: healability as a consequence of donor–acceptor π–π stacking interactions

2009 ◽  
pp. 6717 ◽  
Author(s):  
Stefano Burattini ◽  
Howard M. Colquhoun ◽  
Justin D. Fox ◽  
Donia Friedmann ◽  
Barnaby W. Greenland ◽  
...  
Keyword(s):  
Polymer System ◽  
Supramolecular Polymer ◽  
Stacking Interactions ◽  
Π Stacking ◽  
Donor Acceptor

scholarly journals G-Quadruplex binding optimization by gold(iii) insertion into the center of a porphyrin

2019 ◽  
Vol 48 (18) ◽  
pp. 6091-6099 ◽  
Author(s):  
Angélique Pipier ◽  
Aurore De Rache ◽  
Coralie Modeste ◽  
Samir Amrane ◽  
Emmanuelle Mothes-Martin ◽  
...  
Keyword(s):  
Positive Charge ◽  
Planar Geometry ◽  
Stacking Interactions ◽  
Π Stacking ◽  
Square Planar ◽  
G Quadruplex

Gold(iii) porphyrins have a square planar geometry and an extra positive charge, compatible with stronger electrostatic and π-stacking interactions.

The engineering of stilbazolium/iodocuprate hybrids with optical/electrical performances by modulating inter-molecular charge transfer among H-aggregated chromophores

2020 ◽  
Vol 7 (6) ◽  
pp. 1451-1466 ◽  
Author(s):  
Wei Wu ◽  
Xiang-Ling Lin ◽  
Qian Liu ◽  
Yan He ◽  
You-Ren Huang ◽  
...  
Keyword(s):  
Charge Transfer ◽  
Stacking Interactions ◽  
Face To Face ◽  
Electrical Bistability ◽  
Π Stacking ◽  
Molecular Charge

Good electrical bistability performances in stilbazolium/iodocuprate hybrids stem from the better face-to-face π⋯π stacking interactions induced by the substituents with appropriate lengths and electronic natures.

scholarly journals High resolution crystal structure of a KRAS promoter G-quadruplex reveals a dimer with extensive poly-A π-stacking interactions for small-molecule recognition

2020 ◽  
Vol 48 (10) ◽  
pp. 5766-5776 ◽  
Author(s):  
Arnold Ou ◽  
Jason W Schmidberger ◽  
Katie A Wilson ◽  
Cameron W Evans ◽  
Jessica A Hargreaves ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
High Resolution ◽  
Molecular Dynamics Simulations ◽  
Small Molecule ◽  
Rational Design ◽  
Stacking Interactions ◽  
Π Stacking ◽  
G Quadruplex ◽  
Dynamics Simulations

Abstract Aberrant KRAS signaling is a driver of many cancers and yet remains an elusive target for drug therapy. The nuclease hypersensitive element of the KRAS promoter has been reported to form secondary DNA structures called G-quadruplexes (G4s) which may play important roles in regulating KRAS expression, and has spurred interest in structural elucidation studies of the KRAS G-quadruplexes. Here, we report the first high-resolution crystal structure (1.6 Å) of a KRAS G-quadruplex as a 5′-head-to-head dimer with extensive poly-A π-stacking interactions observed across the dimer. Molecular dynamics simulations confirmed that the poly-A π-stacking interactions are also maintained in the G4 monomers. Docking and molecular dynamics simulations with two G4 ligands that display high stabilization of the KRAS G4 indicated the poly-A loop was a binding site for these ligands in addition to the 5′-G-tetrad. Given sequence and structural variability in the loop regions provide the opportunity for small-molecule targeting of specific G4s, we envisage this high-resolution crystal structure for the KRAS G-quadruplex will aid in the rational design of ligands to selectively target KRAS.

scholarly journals Design, Synthesis and Characterization of Cyclic NU172 Analogues: A Biophysical and Biological Insight

2020 ◽  
Vol 21 (11) ◽  
pp. 3860 ◽  
Author(s):  
Claudia Riccardi ◽  
Albert Meyer ◽  
Jean-Jacques Vasseur ◽  
Domenico Cavasso ◽  
Irene Russo Krauss ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Design Synthesis ◽  
Conformational Constraints ◽  
Biological Insight ◽  
Human Thrombin ◽  
Nuclease Resistance ◽  
Biophysical Techniques ◽  
Ligation Method

NU172—a 26-mer oligonucleotide able to bind exosite I of human thrombin and inhibit its activity—was the first aptamer to reach Phase II clinical studies as an anticoagulant in heart disease treatments. With the aim of favoring its functional duplex-quadruplex conformation and thus improving its enzymatic stability, as well as its thrombin inhibitory activity, herein a focused set of cyclic NU172 analogues—obtained by connecting its 5′- and 3′-extremities with flexible linkers—was synthesized. Two different chemical approaches were exploited in the cyclization procedure, one based on the oxime ligation method and the other on Cu(I)-assisted azide-alkyne cycloaddition (CuAAC), affording NU172 analogues including circularizing linkers with different length and chemical nature. The resulting cyclic NU172 derivatives were characterized using several biophysical techniques (ultraviolet (UV) and circular dichroism (CD) spectroscopies, gel electrophoresis) and then investigated for their serum resistance and anticoagulant activity in vitro. All the cyclic NU172 analogues showed higher thermal stability and nuclease resistance compared to unmodified NU172. These favorable properties were, however, associated with reduced—even though still significant—anticoagulant activity, suggesting that the conformational constraints introduced upon cyclization were somehow detrimental for protein recognition. These results provide useful information for the design of improved analogues of NU172 and related duplex-quadruplex structures.

Sign in / Sign up

Export Citation Format

Share Document