Structure–Activity Relationship Study of a Potent α‐Thrombin Binding Aptamer Incorporating Hexitol Nucleotides

Fenza, Maria De; Eremeeva, Elena; Troisi, Romualdo; Yang, Hui; Esposito, Anna; Sica, F.; Herdewijn, Piet; D’Alonzo, Daniele; Guaragna, Annalisa

doi:10.1002/chem.202001504

Cited by 18 publications

(15 citation statements)

References 74 publications

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“…For all the oligonucleotides, a sigmoidal decrease of the absorbance at 295 nm was found upon increasing the temperature (Figure 2, panel c and d, respectively for the K + -and Na + -rich buffers), in agreement with the unfolding of the G4 domain [66,69,70], while the heating processes monitored at 260 nm (Figure S8, panel a and b, respectively for the K + -and Na + -rich buffers) produced hyperchromic effects upon melting, as generally observed for duplex unfolding [49][50][51]68].…”

Section: Uv Spectroscopy Analysis: Thermal Difference Spectra and Uv Thermal Denaturation/renaturation Measurementssupporting

confidence: 81%

“…Then, UV-monitored thermal denaturation/renaturation experiments were performed to study the thermal stability of both the G-quadruplex and duplex domains of the cyclic NU172 analogues in comparison with NU172 and its "nude" G4 motif NU. It was previously shown, in fact, that the UV-melting curves monitored at 295 and 260 nm give information respectively on the unfolding of the G-quadruplex and duplex domains of the bimodular aptamers [49][50][51]68].…”

Section: Uv Spectroscopy Analysis: Thermal Difference Spectra and Uv Thermal Denaturation/renaturation Measurementsmentioning

confidence: 99%

“…Preliminary biophysical investigations on NU172 demonstrated a strong mutual influence of each domain on the stability of the other [48][49][50][51]. More recently, Troisi et al solved the crystallographic structure of the thrombin-NU172 complex, providing a deep insight into the aptamer folding and its binding to thrombin exosite I, which takes advantage of all three loops of the G4 module [52], due to a peculiar conformation involving the connecting residues as well.…”

Section: Introductionmentioning

confidence: 99%

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

Riccardi

Meyer

Vasseur

et al. 2020

IJMS

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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.

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Section: Uv Spectroscopy Analysis: Thermal Difference Spectra and Uv Thermal Denaturation/renaturation Measurementssupporting

confidence: 81%

Section: Uv Spectroscopy Analysis: Thermal Difference Spectra and Uv Thermal Denaturation/renaturation Measurementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Riccardi

Meyer

Vasseur

et al. 2020

IJMS

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show abstract

“…Considering the challenges associated with the short in vivo half-life, recently, De Fenza et al incorporated some of the critical NU172 nucleotides (at the T9 and G18 positions) with hexitol-based nucleotides to assess their effect on NU172 anticoagulant activity, binding affinity, and plasma half-life [ 48 ]. They found that incorporating these bases slightly improved the NU172 anticoagulant properties.…”

Section: Extrinsic and Common Pathway Aptamersmentioning

confidence: 99%

Overview of the Therapeutic Potential of Aptamers Targeting Coagulation Factors

Liu

Zaman

Fortenberry

2021

IJMS

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Aptamers are single-stranded DNA or RNA sequences that bind target molecules with high specificity and affinity. Aptamers exhibit several notable advantages over protein-based therapeutics. Aptamers are non-immunogenic, easier to synthesize and modify, and can bind targets with greater affinity. Due to these benefits, aptamers are considered a promising therapeutic candidate to treat various conditions, including hematological disorders and cancer. An active area of research involves developing aptamers to target blood coagulation factors. These aptamers have the potential to treat cardiovascular diseases, blood disorders, and cancers. Although no aptamers targeting blood coagulation factors have been approved for clinical use, several aptamers have been evaluated in clinical trials and many more have demonstrated encouraging preclinical results. This review summarized our knowledge of the aptamers targeting proteins involved in coagulation, anticoagulation, fibrinolysis, their extensive applications as therapeutics and diagnostics tools, and the challenges they face for advancing to clinical use.

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“…Our approach exploits the well-known finding that the quality of host-guest interactions benefits from the increase in the preorganization of the guest, since no entropy penalty is involved in the binding process. As demonstrative examples, conformationally restricted nucleosides bearing a six-membered sugar unit have already been found to hold an excellent biomimetic potential in various therapeutic contexts [ 38 , 39 ], as a result of the resemblance of natural ribofuranosyl nucleosides in their bioactive conformations [ 40 ]. Accordingly, following our longstanding interest in the identification of conformationally restricted molecules with biomimetic properties [ 39 , 41 , 42 , 43 , 44 , 45 , 46 ], we undertook the synthesis of novel Immucillin-A and Immucillin-H analogues, i.e., polyhydroxylated piperidine nucleosides 3 and 4 ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

et al. 2021

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The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.

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Structure–Activity Relationship Study of a Potent α‐Thrombin Binding Aptamer Incorporating Hexitol Nucleotides

Abstract: Supporting information for this article is given via a link at the end of the document.

Cited by 18 publications

References 74 publications

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

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

Overview of the Therapeutic Potential of Aptamers Targeting Coagulation Factors

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

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