Multivalent Aptamers: Versatile Tools for Diagnostic and Therapeutic Applications

Vorobyeva, Mariya; Vorobjev, P. E.; Venyaminova, Alya G.

doi:10.3390/molecules21121613

Cited by 95 publications

(64 citation statements)

References 82 publications

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“…These are not the unique literature examples of aptamer optimization obtained by dimerization of known aptamer sequences. Indeed, in the last decade a number of works described improved aptamers realized by engineering bivalent or multivalent analogues of the selected oligonucleotide, not only for VEGF, but also for thrombin [19,[22][23][24][25][26][27], mIgM (B-cell receptor) [28,29], and other biologically relevant targets [30][31][32], so that this strategy can be considered among those of choice to increase the overall efficacy of selected aptamers [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

Riccardi

Musumeci

Platella

et al. 2020

IJMS

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In the optimization process of nucleic acid aptamers, increased affinity and/or activity are generally searched by exploring structural analogues of the lead compound. In many cases, promising results have been obtained by dimerization of the starting aptamer. Here we studied a focused set of covalent dimers of the G-quadruplex (G4) forming anti-Vascular Endothelial Growth Factor (VEGF) V7t1 aptamer with the aim of identifying derivatives with improved properties. In the design of these covalent dimers, connecting linkers of different chemical nature, maintaining the same polarity along the strand or inverting it, have been introduced. These dimeric aptamers have been investigated using several biophysical techniques to disclose the conformational behavior, molecularity and thermal stability of the structures formed in different buffers. This in-depth biophysical characterization revealed the formation of stable G4 structures, however in some cases accompanied by alternative tridimensional arrangements. When tested for their VEGF165 binding and antiproliferative activity in comparison with V7t1, these covalent dimers showed slightly lower binding ability to the target protein but similar if not slightly higher antiproliferative activity on human breast adenocarcinoma MCF-7 cells. These results provide useful information for the design of improved dimeric aptamers based on further optimization of the linker joining the two consecutive V7t1 sequences.

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Section: Introductionmentioning

confidence: 99%

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

Riccardi

Musumeci

Platella

et al. 2020

IJMS

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“…Such multivalent presentations of OAs may also be useful in a wide variety of additional applications in which strong avidity and specificity are desired, ranging from targeted drug delivery to imaging. 6,7,20,21…”

Section: Resultsmentioning

confidence: 99%

Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency

Martin

Douaisi

Arsiwala

et al. 2018

IJN

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PurposeWe are interested in designing a modular strategy for creating potent multivalent ligands, which frequently can be used as effective inhibitors of undesired biomolecular interactions. For example, such inhibitors might prevent the self-assembly of bacterial toxins or the attachment of a virus to its host cell receptors.MethodsWe used a biocompatible polyamino acid polymer as a scaffold for grafting multiple copies of an oligonucleotide aptamer (OA). Specifically, the carboxylates on the side chains of polyglutamic acid (PGA) were modified with a thiol-reactive linker, N-aminoethyl maleimide (AEM), and thiol-functionalized OAs were attached to the maleimide moieties. The resulting conjugates were tested for their ability to compete with and inhibit the binding of unconjugated monovalent OAs to the target cell receptor.ResultsMultivalent PGA–OA conjugates with low, medium, and high valency were successfully prepared. The varying valency and successful purification to remove unconjugated OAs were confirmed by polyacrylamide gel electrophoresis. The resulting purified conjugates inhibited the binding of unconjugated monovalent OAs, and the measured half maximal inhibitory concentration (IC50) values corresponded to a 38–88-fold enhancement of potency on a per-aptamer basis, relative to OA alone.ConclusionMultivalent conjugation of OA ligands has potential as a generally useful way to improve the potency of the interaction between the ligand and its target receptor. We have demonstrated this principle with a known OA as a proof of concept as well a synthetic strategy that can be used to synthesize multivalent conjugates of other OAs.

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“…Simply, connecting identical aptamers should increase affinity to its target since it increases the number of contact points. The connection of different aptamers can also lead to an increase in versatility [160].…”

Section: Multivalent and Dimerization Of Aptamersmentioning

confidence: 99%

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

et al. 2019

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Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems. Molecules 2020, 25, 3 2 of 51 molecules [2]. Nowadays, the aptamer field covers various biomedical applications, including [3], therapeutic [4-6], aptasensors [7], biosensors [8,9], diagnostic [10,11], and imaging systems [12].Aptamers need to be stabilized for in vivo use against nuclease degradation, and their small size makes them susceptible to renal filtration. Aptamers' stabilization can be attained by chemically modifying them using different approaches. Moreover, introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of aptamers and thereby their target spectrum [12]. Modified aptamers may show improved chemical diversity relative to aptamers composed entirely of natural DNA or RNA nucleotides and expand their applications in diagnostics, therapeutics, and nanotechnology [1].Chemical modifications of aptamer oligonucleotides are needed mainly to enhance their resistance to nuclease degradation and lowering their renal filtration. Additionally, chemical modifications, in some cases, may increase the aptamer-binding affinity [13]. Many approaches have been introduced to promote the stability of aptamers without altering their binding affinity and specificity against their targets. These approaches include chemical modification of the phosphate...

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Multivalent Aptamers: Versatile Tools for Diagnostic and Therapeutic Applications

Cited by 95 publications

References 82 publications

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

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Multivalent Aptamers: Versatile Tools for Diagnostic and Therapeutic Applications

Cited by 95 publications

References 82 publications

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

Synthesis of multivalent polymer&ndash;aptamer conjugates with enhanced inhibitory potency

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

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Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency