Molecules

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12 pages, 2282 KiB

Open AccessArticle

Common Secondary and Tertiary Structural Features of Aptamer–Ligand Interaction Shared by RNA Aptamers with Different Primary Sequences

by Muslum Ilgu, Shuting Yan, Ryan M. Khounlo, Monica H. Lamm and Marit Nilsen-Hamilton

Molecules 2019, 24(24), 4535; https://doi.org/10.3390/molecules24244535 - 11 Dec 2019

Cited by 8 | Viewed by 3481

Abstract

Aptamer selection can yield many oligonucleotides with different sequences and affinities for the target molecule. Here, we have combined computational and experimental approaches to understand if aptamers with different sequences but the same molecular target share structural and dynamical features. NEO1A, with a [...] Read more.

Aptamer selection can yield many oligonucleotides with different sequences and affinities for the target molecule. Here, we have combined computational and experimental approaches to understand if aptamers with different sequences but the same molecular target share structural and dynamical features. NEO1A, with a known NMR-solved structure, displays a flexible loop that interacts differently with individual aminoglycosides, its ligand affinities and specificities are responsive to ionic strength, and it possesses an adenosine in the loop that is critical for high-affinity ligand binding. NEO2A was obtained from the same selection and, although they are only 43% identical in overall sequence, NEO1A and NEO2A share similar loop sequences. Experimental analysis by 1D NMR and 2-aminopurine reporters combined with molecular dynamics modeling revealed similar structural and dynamical characteristics in both aptamers. These results are consistent with the hypothesis that the target ligand drives aptamer structure and also selects relevant dynamical characteristics for high-affinity aptamer-ligand interaction. Furthermore, they suggest that it might be possible to “migrate” structural and dynamical features between aptamer group members with different primary sequences but with the same target ligand. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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14 pages, 1637 KiB

Open AccessArticle

Bimodular Antiparallel G-Quadruplex Nanoconstruct with Antiproliferative Activity

by Olga Antipova, Nadezhda Samoylenkova, Ekaterina Savchenko, Elena Zavyalova, Alexander Revishchin, Galina Pavlova and Alexey Kopylov

Molecules 2019, 24(19), 3625; https://doi.org/10.3390/molecules24193625 - 08 Oct 2019

Cited by 9 | Viewed by 2758

Abstract

Oligonucleotides with an antiproliferative activity for human cancer cells have attracted attention over the past decades; many of them have a G-quadruplex structure (GQ), and a cryptic target. In particular, DNA oligonucleotide HD1, a minimal GQ, could inhibit proliferation of some cancer cell [...] Read more.

Oligonucleotides with an antiproliferative activity for human cancer cells have attracted attention over the past decades; many of them have a G-quadruplex structure (GQ), and a cryptic target. In particular, DNA oligonucleotide HD1, a minimal GQ, could inhibit proliferation of some cancer cell lines. The HD1 is a 15-nucleotide DNA oligonucleotide that folds into a minimal chair-like monomolecular antiparallel GQ structure. In this study, for eight human cancer cell lines, we have analyzed the antiproliferative activities of minimal bimodular DNA oligonucleotide, biHD1, which has two HD1 modules covalently linked via single T-nucleotide residue. Oligonucleotide biHD1 exhibits a dose-dependent antiproliferative activity for lung cancer cell line RL-67 and cell line of central nervous system cancer U87 by MTT-test and Ki-67 immunoassay. The study of derivatives of biHD1 for the RL-67 and U87 cell lines revealed a structure-activity correlation of GQ folding and antiproliferative activity. Therefore, a covalent joining of two putative GQ modules within biHD1 molecule provides the antiproliferative activity of initial HD1, opening a possibility to design further GQ multimodular nanoconstructs with antiproliferative activity—either as themselves or as carriers. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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18 pages, 1992 KiB

Open AccessArticle

Energy Transfer as A Driving Force in Nucleic Acid–Protein Interactions

by Elena Zavyalova and Alexey Kopylov

Molecules 2019, 24(7), 1443; https://doi.org/10.3390/molecules24071443 - 11 Apr 2019

Cited by 2 | Viewed by 2876

Abstract

Many nucleic acid–protein structures have been resolved, though quantitative structure-activity relationship remains unclear in many cases. Thrombin complexes with G-quadruplex aptamers are striking examples of a lack of any correlation between affinity, interface organization, and other common parameters. Here, we tested the hypothesis [...] Read more.

Many nucleic acid–protein structures have been resolved, though quantitative structure-activity relationship remains unclear in many cases. Thrombin complexes with G-quadruplex aptamers are striking examples of a lack of any correlation between affinity, interface organization, and other common parameters. Here, we tested the hypothesis that affinity of the aptamer–protein complex is determined with the capacity of the interface to dissipate energy of binding. Description and detailed analysis of 63 nucleic acid–protein structures discriminated peculiarities of high-affinity nucleic acid–protein complexes. The size of the amino acid sidechain in the interface was demonstrated to be the most significant parameter that correlates with affinity of aptamers. This observation could be explained in terms of need of efficient energy transfer from interacting residues. Application of energy dissipation theory provided an illustrative tool for estimation of efficiency of aptamer–protein complexes. These results are of great importance for a design of efficient aptamers. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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Review

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51 pages, 6663 KiB

Open AccessReview

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

by Fadwa Odeh, Hamdi Nsairat, Walhan Alshaer, Mohammad A. Ismail, Ezaldeen Esawi, Baraa Qaqish, Abeer Al Bawab and Said I. Ismail

Molecules 2020, 25(1), 3; https://doi.org/10.3390/molecules25010003 - 18 Dec 2019

Cited by 197 | Viewed by 16262

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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13 pages, 1547 KiB

Open AccessReview

Anything You Can Do, I Can Do Better: Can Aptamers Replace Antibodies in Clinical Diagnostic Applications?

by Michelle Bauer, Mia Strom, David S Hammond and Sarah Shigdar

Molecules 2019, 24(23), 4377; https://doi.org/10.3390/molecules24234377 - 30 Nov 2019

Cited by 65 | Viewed by 5894

Abstract

The mainstay of clinical diagnostics is the use of specialised ligands that can recognise specific biomarkers relating to pathological changes. While protein antibodies have been utilised in these assays for the last 40 years, they have proven to be unreliable due to a [...] Read more.

The mainstay of clinical diagnostics is the use of specialised ligands that can recognise specific biomarkers relating to pathological changes. While protein antibodies have been utilised in these assays for the last 40 years, they have proven to be unreliable due to a number of reasons. The search for the ‘perfect’ targeting ligand or molecular probe has been slow, though the description of chemical antibodies, also known as aptamers, nearly 30 years ago suggested a replacement reagent. However, uptake has been slow to progress into the clinical environment. In this review, we discuss the issues associated with antibodies and describe some of the applications of aptamers that have relevancy to the clinical diagnostic environment. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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14 pages, 1041 KiB

Open AccessReview

Aptamers: A Review of Their Chemical Properties and Modifications for Therapeutic Application

by Tatsuo Adachi and Yoshikazu Nakamura

Molecules 2019, 24(23), 4229; https://doi.org/10.3390/molecules24234229 - 21 Nov 2019

Cited by 164 | Viewed by 11212

Abstract

Aptamers are short, single-stranded oligonucleotides that bind to specific target molecules. The shape-forming feature of single-stranded oligonucleotides provides high affinity and excellent specificity toward targets. Hence, aptamers can be used as analogs of antibodies. In December 2004, the US Food and Drug Administration [...] Read more.

Aptamers are short, single-stranded oligonucleotides that bind to specific target molecules. The shape-forming feature of single-stranded oligonucleotides provides high affinity and excellent specificity toward targets. Hence, aptamers can be used as analogs of antibodies. In December 2004, the US Food and Drug Administration approved the first aptamer-based therapeutic, pegaptanib (Macugen), targeting vascular endothelial growth factor, for the treatment of age-related macular degeneration. Since then, however, no aptamer medication for public health has appeared. During these relatively silent years, many trials and improvements of aptamer therapeutics have been performed, opening multiple novel directions for the therapeutic application of aptamers. This review summarizes the basic characteristics of aptamers and the chemical modifications available for aptamer therapeutics. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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27 pages, 3510 KiB

Open AccessReview

G-Quadruplex-Forming Aptamers—Characteristics, Applications, and Perspectives

by Carolina Roxo, Weronika Kotkowiak and Anna Pasternak

Molecules 2019, 24(20), 3781; https://doi.org/10.3390/molecules24203781 - 21 Oct 2019

Cited by 127 | Viewed by 8945

Abstract

G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops length, and localization in the sequence or structure molecularity, G-quadruplexes are highly polymorphic structures showing various folding topologies. They may [...] Read more.

G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops length, and localization in the sequence or structure molecularity, G-quadruplexes are highly polymorphic structures showing various folding topologies. They may be formed in the human genome where they are believed to play a pivotal role in the regulation of multiple biological processes such as replication, transcription, and translation. Thus, natural G-quadruplex structures became prospective targets for disease treatment. The fast development of systematic evolution of ligands by exponential enrichment (SELEX) technologies provided a number of G-rich aptamers revealing the potential of G-quadruplex structures as a promising molecular tool targeted toward various biologically important ligands. Because of their high stability, increased cellular uptake, ease of chemical modification, minor production costs, and convenient storage, G-rich aptamers became interesting therapeutic and diagnostic alternatives to antibodies. In this review, we describe the recent advances in the development of G-quadruplex based aptamers by focusing on the therapeutic and diagnostic potential of this exceptional class of nucleic acid structures. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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23 pages, 795 KiB

Open AccessReview

Inside the Black Box: What Makes SELEX Better?

by Natalia Komarova and Alexander Kuznetsov

Molecules 2019, 24(19), 3598; https://doi.org/10.3390/molecules24193598 - 07 Oct 2019

Cited by 105 | Viewed by 9001

Abstract

Aptamers are small oligonucleotides that are capable of binding specifically to a target, with impressive potential for analysis, diagnostics, and therapeutics applications. Aptamers are isolated from large nucleic acid combinatorial libraries using an iterative selection process called SELEX (Systematic Evolution of Ligands by [...] Read more.

Aptamers are small oligonucleotides that are capable of binding specifically to a target, with impressive potential for analysis, diagnostics, and therapeutics applications. Aptamers are isolated from large nucleic acid combinatorial libraries using an iterative selection process called SELEX (Systematic Evolution of Ligands by EXponential enrichment). Since being implemented 30 years ago, the SELEX protocol has undergone many modifications and improvements, but it remains a laborious, time-consuming, and costly method, and the results are not always successful. Each step in the aptamer selection protocol can influence its results. This review discusses key technical points of the SELEX procedure and their influence on the outcome of aptamer selection. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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22 pages, 3324 KiB

Open AccessReview

Recent Advances in Aptamer Discovery and Applications

by Yang Zhang, Bo Shiun Lai and Mario Juhas

Molecules 2019, 24(5), 941; https://doi.org/10.3390/molecules24050941 - 07 Mar 2019

Cited by 418 | Viewed by 18580

Abstract

Aptamers are short, single-stranded DNA, RNA, or synthetic XNA molecules that can be developed with high affinity and specificity to interact with any desired targets. They have been widely used in facilitating discoveries in basic research, ensuring food safety and monitoring the environment. [...] Read more.

Aptamers are short, single-stranded DNA, RNA, or synthetic XNA molecules that can be developed with high affinity and specificity to interact with any desired targets. They have been widely used in facilitating discoveries in basic research, ensuring food safety and monitoring the environment. Furthermore, aptamers play promising roles as clinical diagnostics and therapeutic agents. This review provides update on the recent advances in this rapidly progressing field of research with particular emphasis on generation of aptamers and their applications in biosensing, biotechnology and medicine. The limitations and future directions of aptamers in target specific delivery and real-time detection are also discussed. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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Other

Jump to: Research, Review

14 pages, 310 KiB

Open AccessPerspective

Predicting Future Prospects of Aptamers in Field-Effect Transistor Biosensors

by Cao-An Vu and Wen-Yih Chen

Molecules 2020, 25(3), 680; https://doi.org/10.3390/molecules25030680 - 05 Feb 2020

Cited by 23 | Viewed by 5129

Abstract

Aptamers, in sensing technology, are famous for their role as receptors in versatile applications due to their high specificity and selectivity to a wide range of targets including proteins, small molecules, oligonucleotides, metal ions, viruses, and cells. The outburst of field-effect transistors provides [...] Read more.

Aptamers, in sensing technology, are famous for their role as receptors in versatile applications due to their high specificity and selectivity to a wide range of targets including proteins, small molecules, oligonucleotides, metal ions, viruses, and cells. The outburst of field-effect transistors provides a label-free detection and ultra-sensitive technique with significantly improved results in terms of detection of substances. However, their combination in this field is challenged by several factors. Recent advances in the discovery of aptamers and studies of Field-Effect Transistor (FET) aptasensors overcome these limitations and potentially expand the dominance of aptamers in the biosensor market. Full article

(This article belongs to the Special Issue Aptamers: Successes, Limitations and Future Directions)

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