A terminal functionalization strategy reveals unusual binding abilities of anti-thrombin anticoagulant aptamers

Troisi, Romualdo; Riccardi, Claudia; Carvasal, Kévan Pérez de; Smietana, Michaël; Morvan, François; Vecchio, Pompea Del; Montesarchio, Daniela; Sica, F.

doi:10.1016/j.omtn.2022.11.007

Cited by 9 publications

(13 citation statements)

References 67 publications

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“…This impressive result was attributed to the CT interaction combined with the solvophobic effect as it has been demonstrated that in water, NDI and DAN have an association constant that is 10- to 100-fold higher than their respective self-association . In another study, we showed that in crystals of the aptamer:thrombin complex, NDI and DAN form an alternate stacking starting from an NDI close to the DNA . These data confirmed molecular modeling studies that predicted alternate stacking. , …”

Section: Introductionsupporting

confidence: 79%

“…44 In another study, we showed that in crystals of the aptamer:thrombin complex, NDI and DAN form an alternate stacking starting from an NDI close to the DNA. 45 These data confirmed molecular modeling studies that predicted alternate stacking. 42,46 Along with our previous works devoted to the synthesis of DAN-NDI-based supramolecular structures as an alternated sequence, 42 or as a duplex formed by recognition of a hexaDAN and a hexaNDI, 46 ■ RESULTS AND DISCUSSION Oligomers Synthesis.…”

Section: ■ Introductionsupporting

confidence: 77%

“…In addition, a hairpin with a DAN:NDI loop and a DAN:NDI pair at the end exhibits a very stable structure with Tm values above 90 °C. It has been shown that in crystals of an aptamer closed by two NDIs and two DANs, DANs and NDIs form an alternate stacking starting from an NDI close to the DNA, 45 so we can assume that a similar arrangement occurred in the current 3. Curve fits data were averaged from fits of two melting and two annealing curves.…”

Section: ■ Conclusionmentioning

confidence: 94%

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Stabilization of DNA Duplexes and Hairpins by Charge-Transfer Interactions Using DAN:NDI Pairs

Pérez de Carvasal,

Nicollet,

Smietana

et al. 2023

Langmuir

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Electron-rich 1,5-dialkoxynaphthalene (DAN) and electron-deficient 1,8,4,5-naphthalenetetracarboxylic diimide (NDI) are known to interact through the formation of charge-transfer complexes. The introduction of DAN and NDI into various DNA duplexes and hairpins was investigated by ultraviolet (UV) melting curve analysis. The positioning of the DAN:NDI pair was found to strongly influence the stability of DNA duplex and hairpins. In particular, while the introduction of one DAN/NDI pair in front of each other in the center of a DNA duplex led to a decrease of the thermal stability (ΔTm – 6 °C), the addition of a second pair restored or even increased the stability. In contrast, the introduction of DAN:NDI pairs at the end of a duplex always induced a strong stabilization (ΔTm up to +20 °C). Finally, a DAN:NDI pair positioned in the loop of a hairpin induced a stronger stabilization than a T4 loop (ΔTm + 10 °C). Based on charge-transfer interactions, the strong stabilizations observed allow the preparation of highly stabilized DNA nanostructures opening the way to numerous applications in nanotechnology.

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Section: Introductionsupporting

confidence: 79%

Section: ■ Introductionsupporting

confidence: 77%

Section: ■ Conclusionmentioning

confidence: 94%

See 1 more Smart Citation

Stabilization of DNA Duplexes and Hairpins by Charge-Transfer Interactions Using DAN:NDI Pairs

Pérez de Carvasal,

Nicollet,

Smietana

et al. 2023

Langmuir

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“…To address this issue, we propose a screening methodology grounded in a library of short DNA sequences characterized by relatively reduced structural complexity. Extensive structural studies have revealed that aptamer recognition of target molecules often relies on a limited number of key bases, such as the aptamers for Thrombin, GRK2, and Hfq [43][44][45] . Thus, a library of 1024 (4 5 ) single-stranded DNA (ssDNA) sequences with 5 nucleotides was generated for initial virtual screening.…”

Section: Development Of Blocker-selex Pipelinementioning

confidence: 99%

“…By employing this strategy, we have effectively engineered inhibitory aptamers that possess the ability to disrupt the interactions between RNAP2 and SCAF4 or SCAF8 proteins, which were previously considered "undruggable" using small-molecule inhibitors owing to the lack of "conventional drug-binding" pockets at the interface of SCAF4/SCAF8. Notably, aptamers exhibit target recognition capabilities that do not necessitate the presence of a "conventional drug-binding" pocket 43,[63][64][65][66][67][68] . This characteristic makes aptamers ideal chemical tools for intervening in "undruggable" protein-protein/DNA interactions.…”

Section: Blocker-selex Pipeline Is Feasible Against Wdr5-myc Interactionmentioning

confidence: 99%

Blocker-SELEX: A Structure-guided Strategy for Developing Inhibitory Aptamers Disrupting Undruggable Transcription Factor Interactions

Li,

Liu,

Zhang

et al. 2024

Preprint

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SummaryDespite the well-established significance of transcription factors (TFs) in pathogenesis, their utilization as pharmacological targets has been limited by the inherent challenges associated with modulating their protein-protein and protein-DNA interactions. The lack of defined small-molecule binding pockets and the nuclear localization of TFs do not favor the use of small-molecule inhibitors, or neutral antibodies, in blocking TF interactions. Aptamers are short oligonucleotides exhibiting high affinity and specificity for a diverse range of targets. Large molecular weights, expansive blocking surfaces and efficient cellular internalization make aptamers a compelling molecular tool for use as traditional TF interaction modulators. Here, we report a structure-guided design strategy called Blocker-SELEX to develop inhibitory aptamers (iAptamer) that selectively block TF interactions. Our approach led to the discovery of iAptamers that cooperatively disrupts SCAF4/SCAF8-RNA Polymerase II (RNAP2) interactions, thereby dysregulating RNAP2-dependent gene expression and splicing and, in turn, leading to the impairment of cell proliferation. This approach was further applied to develop iAptamers to efficiently block WDR5-MYC interaction with a nexus in cancer. Taken together, our study highlights the potential of Blocker-SELEX in developing iAptamers that effectively disrupt potentially pathogenic TF interactions with attendant implications for iAptamers as chemical tools for use in the study of biological functions of TF interactions, but also for potential use in nucleic acids drug discovery.

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Probing naphthalene diimide and 3-hydroxypropylphosphate as end-conjugating moieties for improved thrombin binding aptamers: Structural and biological effects

Riccardi,

Pérez de Carvasal,

Platella

et al. 2023

Bioorganic Chemistry

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A terminal functionalization strategy reveals unusual binding abilities of anti-thrombin anticoagulant aptamers

Cited by 9 publications

References 67 publications

Stabilization of DNA Duplexes and Hairpins by Charge-Transfer Interactions Using DAN:NDI Pairs

Stabilization of DNA Duplexes and Hairpins by Charge-Transfer Interactions Using DAN:NDI Pairs

Blocker-SELEX: A Structure-guided Strategy for Developing Inhibitory Aptamers Disrupting Undruggable Transcription Factor Interactions

Probing naphthalene diimide and 3-hydroxypropylphosphate as end-conjugating moieties for improved thrombin binding aptamers: Structural and biological effects

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