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Synthesis and Applications of Oligonucleotide Conjugates

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 April 2017) | Viewed by 79569

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Prof. Dr. Harri Lönnberg

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Department of Chemistry, University of Turku, 20014 Turku, Finland
Interests: kinetic studies on chemical models of ribonucleases and ribozymes; synthesis and application of oligonucleotide conjugates; pro-drug strategies for phosphoester drugs; novel approaches for medium scale synthesis of oligonucleotides
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Dear Colleagues,

Conjugates of oligonucleotides bearing unnatural organic structures or constituents of other biopolymers have found an increasing number of applications as research tools for cell biology. The list of conjugate groups aimed at providing the oligonucleotide with some novel property is extensive. Reporter groups, such as fluorescent dyes and spin-labels, allow for sensitive detection of oligonucleotides. Chemically or photochemically reactive groups may enable site selective cleavage of the target sequence or cross-linking with the target. Intercalators stabilize double helices and groove binders may be exploited in their recognition. Oligonucleotides conjugated to chelating groups serve as target specific carriers of metal ions, finding applications both in diagnostics and chemotherapy. Last, but not least, covalent conjugation of oligonucleotides to molecules that expectedly facilitate internalization, targets the conjugate to a specific cell-type or improves the parmacokinetics offers a possible way to combat against the most severe shortcoming of therapeutic oligonucleotides, viz. inefficient cellular uptake and subsequent release from endosomes to cytoplasm. For this purpose, lipid, carbohydrate, peptide, aptamer and small molecule conjugates are used. It may also be possible to control the intracellular traffic of oligonucleotide drugs by conjugation. In many cases, conjugation through a biodegradable linker is desirable, or biodegradable protecting groups are used. The synthesis of oligonucleotide conjugates is challenging. Synthesis on a single solid support is possible, but usually the conventional protocol of oligonucleotide synthesis has to be modified. Alternatively, bio-orthogonal post-synthetic conjugation in solution may be applied. The present Special Issue is aimed at covering new synthetic methodologies of oligonucleotide conjugates, as well as their novel applications.

Prof. Dr. Harri Lönnberg
Guest Editor

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Keywords

oligonucleotides
synthesis
conjugation
delivery
antisense

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Synthesis and Applications of Oligonucleotide Conjugate II in Molecules (9 articles)

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Editorial

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Open AccessEditorial

Special Issue “Synthesis and Applications of Oligonucleotide Conjugates”

by Harri Lönnberg

Molecules 2017, 22(10), 1700; https://doi.org/10.3390/molecules22101700 - 13 Oct 2017

Viewed by 3213

Abstract

The underlying idea of oligonucleotide conjugates is to provide oligonucleotide with some novel property [...] Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

Research

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4665 KiB

Open AccessArticle

High Boron-loaded DNA-Oligomers as Potential Boron Neutron Capture Therapy and Antisense Oligonucleotide Dual-Action Anticancer Agents

by Damian Kaniowski, Katarzyna Ebenryter-Olbińska, Milena Sobczak, Błażej Wojtczak, Sławomir Janczak, Zbigniew J. Leśnikowski and Barbara Nawrot

Molecules 2017, 22(9), 1393; https://doi.org/10.3390/molecules22091393 - 23 Aug 2017

Cited by 27 | Viewed by 7278

Abstract

Boron cluster-modified therapeutic nucleic acids with improved properties are of interest in gene therapy and in cancer boron neutron capture therapy (BNCT). High metallacarborane-loaded antisense oligonucleotides (ASOs) targeting epidermal growth factor receptor (EGFR) were synthesized through post-synthetic Cu (I)-assisted “click” conjugation of alkyne-modified DNA-oligonucleotides with a boron cluster alkyl azide component. The obtained oligomers exhibited increased lipophilicity compared to their non-modified precursors, while their binding affinity to complementary DNA and RNA strands was slightly decreased. Multiple metallacarborane residues present in the oligonucleotide chain, each containing 18 B-H groups, enabled the use of IR spectroscopy as a convenient analytical method for these oligomers based on the diagnostic B-H signal at 2400–2650 cm⁻¹. The silencing activity of boron cluster-modified ASOs used at higher concentrations was similar to that of unmodified oligonucleotides. The screened ASOs, when used in low concentrations (up to 50 μM), exhibited pro-oxidative properties by inducing ROS production and an increase in mitochondrial activities in HeLa cells. In contrast, when used at higher concentrations, the ASOs exhibited anti-oxidative properties by lowering ROS species levels. In the HeLa cells (tested in the MTT assay) treated (without lipofectamine) or transfected with the screened compounds, the mitochondrial activity remained equal to the control level or only slightly changed (±30%). These findings may be useful in the design of dual-action boron cluster-modified therapeutic nucleic acids with combined antisense and anti-oxidant properties. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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1842 KiB

Open AccessCommunication

Synthesis of 5′-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies

by Isaiah Cedillo, Dana Chreng, Elyse Engle, Lijian Chen, Andrew K. McPherson and Andrew A. Rodriguez

Molecules 2017, 22(8), 1356; https://doi.org/10.3390/molecules22081356 - 15 Aug 2017

Cited by 24 | Viewed by 12506

Abstract

Antisense oligonucleotides (ASOs) conjugated to triantennary N-acetyl galactosamine (GalNAc) ligands represent an emerging approach to antisense therapy. Our current generation of GalNAc-ASO conjugates link the GalNAc to the 5′-terminus of the ASO. The conjugation reaction can be accomplished using solution-phase or solid-phase techniques. Here we show a direct comparison of a solution-phase and a solid-phase conjugation strategy. The solution-phase approach, using amine-pentafluorophenyl (PFP) ester coupling, is higher yielding and gives material of slightly higher purity, but requires several additional unit operations and longer production time. The solid-phase approach, using a protected GalNAc ligand phosphoramidite, is more expedient, but results in lower yield and purity. Both strategies efficiently deliver conjugated material in excellent purity. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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2813 KiB

Open AccessArticle

Oligonucleotides and ND-FISH Displaying Different Arrangements of Tandem Repeats and Identification of Dasypyrum villosum Chromosomes in Wheat Backgrounds

by Zhiqiang Xiao, Shuyao Tang, Ling Qiu, Zongxiang Tang and Shulan Fu

Molecules 2017, 22(6), 973; https://doi.org/10.3390/molecules22060973 - 14 Jun 2017

Cited by 40 | Viewed by 5778

Abstract

Oligonucleotide probes and the non-denaturing fluorescence in situ hybridization (ND-FISH) technique are widely used to analyze plant chromosomes because they are convenient tools. New oligonucleotide probes, Oligo-Ku, Oligo-3B117.1, Oligo-3B117.2, Oligo-3B117.2.1, Oligo-3B117.3, Oligo-3B117.4, Oligo-3B117.5, Oligo-3B117.6, Oligo-pTa71A-1, Oligo-pTa71A-2, Oligo-pTa71B-1, Oligo-pTa71B-2, Oligo-pTa71C-1, Oligo-pTa71C-2, Oligo-pTa71C-3 and Oligo-pTa71D were designed based on the repetitive sequences KU.D15.15, pSc119.2-like sequence 3B117 and pTa71. Oligonucleotide probe (GT)₇ was also used. Oligo-Ku and (GT)₇ can be together used to identify Dasypyrum villosum from wheat chromosomes and to distinguish individual D. villosum chromosomes. The oligonucleotide probes that were derived from the same repeat sequence displayed different signal intensity and hybridization sites on the same chromosomes. Both the length and the nucleotide composition of oligonucleotide probes determined their signal intensity. For example, Oligo-3B117.2 (25 bp) and Oligo-pTa71A-2 (46 bp) produced the strongest signals on chromosomes of wheat (Triticum aestivum L.), rye (Secale cereale L.), barley (Hordeum vulgare ssp. vulgare) or D. villosum, the signal of Oligo-3B117.4 (18 bp) on the short arm of 7B chromosome was weaker than that of Oligo-3B117.2.1 (15 bp) and Oligo-3B117.3 (16 bp), and Oligo-pTa71A-1 (38 bp) produced the same strong signals as Oligo-pTa71A-2 did on 1B and 6B chromosomes, but its signals on 1R and 1V chromosomes were weaker than the ones of Oligo-pTa71A-2. Oligonucleotide probes and ND-FISH analysis can reflect the distribution and structural statues of different segments of tandem repeats on chromosomes. The possible reasons why different segments derived from the same repeat sequence produced different signal patterns are discussed. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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Open AccessArticle

Development of Optimized Inhibitor RNAs Allowing Multisite-Targeting of the HCV Genome

by Cristina Romero-López, Thomas Lahlali, Beatriz Berzal-Herranz and Alfredo Berzal-Herranz

Molecules 2017, 22(5), 861; https://doi.org/10.3390/molecules22050861 - 22 May 2017

Cited by 10 | Viewed by 4886

Abstract

Engineered multivalent drugs are promising candidates for fighting infection by highly variable viruses, such as HCV. The combination into a single molecule of more than one inhibitory domain, each with its own target specificity and even a different mechanism of action, results in drugs with potentially enhanced therapeutic properties. In the present work, the anti-HCV chimeric inhibitor RNA HH363-10, which has a hammerhead catalytic domain and an aptamer RNA domain, was subjected to an in vitro selection strategy to isolate ten different optimised chimeric inhibitor RNAs. The catalytic domain was preserved while the aptamer RNA domain was evolved to contain two binding sites, one mapping to the highly conserved IIIf domain of the HCV genome’s internal ribosome entry site (IRES), and the other either to IRES domain IV (which contains the translation start codon) or the essential linker region between domains I and II. These chimeric molecules efficiently and specifically interfered with HCV IRES-dependent translation in vitro (with IC₅₀ values in the low µM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved RNA molecules with potential clinical applications. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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Synthesis and Excellent Duplex Stability of Oligonucleotides Containing 2′-Amino-LNA Functionalized with Galactose Units

by Rajesh Kumar, Annika Ries and Jesper Wengel

Molecules 2017, 22(5), 852; https://doi.org/10.3390/molecules22050852 - 21 May 2017

Cited by 8 | Viewed by 7221

Abstract

A convenient method for the preparation of oligonucleotides containing internally-attached galactose and triantennary galactose units has been developed based on click chemistry between 2′-N-alkyne 2′-amino-LNA nucleosides and azido-functionalized galactosyl building blocks. The synthesized oligonucleotides show excellent binding affinity and selectivity towards [...] Read more.

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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2767 KiB

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Detecting and Discriminating Shigella sonnei Using an Aptamer-Based Fluorescent Biosensor Platform

by Myeong-Sub Song, Simranjeet Singh Sekhon, Woo-Ri Shin, Hyung Cheol Kim, Jiho Min, Ji-Young Ahn and Yang-Hoon Kim

Molecules 2017, 22(5), 825; https://doi.org/10.3390/molecules22050825 - 17 May 2017

Cited by 74 | Viewed by 7736

Abstract

In this paper, a Whole-Bacteria SELEX (WB-SELEX) strategy was adopted to isolate specific aptamers against Shigella sonnei. Real-time PCR amplification and post-SELEX experiment revealed that the selected aptmers possessed a high binding affinity and specificity for S. sonnei. Of the 21 aptamers tested, the C(t) values of the SS-3 and SS-4 aptamers (Ct = 13.89 and Ct = 12.23, respectively) had the lowest value compared to other aptamer candidates. The SS-3 and SS-4 aptamers also displayed a binding affinity (K_D) of 39.32 ± 5.02 nM and 15.89 ± 1.77 nM, respectively. An aptamer-based fluorescent biosensor assay was designed to detect and discriminate S. sonnei cells using a sandwich complex pair of SS-3 and SS-4. The detection of S. sonnei by the aptamer based fluorescent biosensor platform consisted of three elements: (1) 5’amine-SS-4 modification in a 96-well type microtiter plate surface (N-oxysuccinimide, NOS) as capture probes; (2) the incubation with S. sonnei and test microbes in functionalized 96 assay wells in parallel; (3) the readout of fluorescent activity using a Cy5-labeled SS-3 aptamer as the detector. Our platform showed a significant ability to detect and discriminate S. sonnei from other enteric species such as E. coli, Salmonella typhimurium and other Shigella species (S. flexneri, S. boydii). In this study, we demonstrated the feasibility of an aptamer sensor platform to detect S. sonnei in a variety of foods and pave the way for its use in diagnosing shigellosis through multiple, portable designs. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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1634 KiB

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Synthesis of Aminoglycoside-2′-O-Methyl Oligoribonucleotide Fusions

by Lotta Granqvist, Andrzej Kraszewski, Ville Tähtinen and Pasi Virta

Molecules 2017, 22(5), 760; https://doi.org/10.3390/molecules22050760 - 8 May 2017

Cited by 3 | Viewed by 5548

Abstract

Phosphoramidite building blocks of ribostamycin (3 and 4), that may be incorporated at any position of the oligonucleotide sequence, were synthesized. The building blocks, together with a previously described neomycin-modified solid support, were applied for the preparation of aminoglycoside-2′-O-methyl oligoribonucleotide fusions. The fusions were used to clamp a single strand DNA sequence (a purine-rich strand of c-Myc promoter 1) to form triple helical 2′-O-methyl RNA/DNA-hybrid constructs. The potential of the aminoglycoside moieties to stabilize the triple helical constructs were studied by UV-melting profile analysis. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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2444 KiB

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Generation and Applications of a DNA Aptamer against Gremlin-1

by Qian Li, Yongwei Huo, Yonghong Guo, Xiaoyan Zheng, Wengang Sun and Zhiming Hao

Molecules 2017, 22(5), 706; https://doi.org/10.3390/molecules22050706 - 28 Apr 2017

Cited by 10 | Viewed by 6931

Abstract

Gremlin-1, a highly conserved glycosylated and phosphorylated secretory protein, plays important roles in diverse biological processes including early embryonic development, fibrosis, tumorigenesis, and renal pathophysiology. Aptamers, which are RNA or DNA single-stranded oligonucleotides capable of binding specifically to different targets ranging from small organics to whole cells, have potential applications in targeted imaging, diagnosis and therapy. In this study, we obtained a DNA aptamer against Gremlin-1 (G-ap49) using in vitro Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Binding assay and dot-blot showed that G-ap49 had high affinity for Gremlin-1. Further experiments indicated that G-ap49 was quite stable in a cell culture system and could be used in South-Western blot analysis, enzyme-linked aptamer sorbent assay (ELASA), and aptamer-based cytochemistry and histochemistry staining to detect Gremlin-1. Moreover, our study demonstrated that G-ap49 is capable of revealing the subcellular localization of Gremlin-1. These data indicate that G-ap49 can be used as an alternative to antibodies in detecting Gremlin-1. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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4052 KiB

Open AccessArticle

Construction and Biological Evaluation of a Novel Integrin α_νβ₃-Specific Carrier for Targeted siRNA Delivery In Vitro

by Xueqi Chen, Meng Liu, Rongfu Wang, Ping Yan, Chunli Zhang, Chao Ma and Lei Yin

Molecules 2017, 22(2), 231; https://doi.org/10.3390/molecules22020231 - 4 Feb 2017

Cited by 6 | Viewed by 5692

Abstract

(1) Background: The great potential of RNA interference (RNAi)-based gene therapy is premised on the effective delivery of small interfering RNAs (siRNAs) to target tissues and cells. Hence, we aimed at developing and examining a novel integrin α_vβ₃-specific delivery carrier for targeted transfection of siRNA to malignant tumor cells; (2) Methods: Arginine-glycine-aspartate motif (RGD) was adopted as a tissue target for specific recognition of integrin α_vβ₃. To enable siRNA binding, a chimeric peptide was synthesized by adding nonamer arginine residues (9R) at the carboxy terminus of cyclic-RGD dimer, designated as c(RGD)₂-9R. The efficiency of 9R peptide transferring siRNA was biologically evaluated in vitro by flow cytometry, confocal microscopy, and Western blot; (3) Results: An optimal 10:1 molar ratio of c(RGD)₂-9R to siRNA was confirmed by the electrophoresis on agarose gels. Both the flow cytometry and confocal microscopy results testified that transfection of c(RGD)₂-9R as an siRNA delivery carrier was obviously higher than the naked-siRNA group. The results of Western blot demonstrated that these 9R peptides were able to transduce siRNA to HepG2 cells in vitro, resulting in efficient gene silencing; and (4) Conclusion: The chimeric peptide of c(RGD)₂-9R can be developed as an effective siRNA delivery carrier and shows potential as a new strategy for RNAi-based gene therapy. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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Review

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Multivalent Aptamers: Versatile Tools for Diagnostic and Therapeutic Applications

by Mariya Vorobyeva, Pavel Vorobjev and Alya Venyaminova

Molecules 2016, 21(12), 1613; https://doi.org/10.3390/molecules21121613 - 25 Nov 2016

Cited by 95 | Viewed by 11527

Abstract

Nucleic acid aptamers generated through an in vitro selection are currently extensively applied as very valuable biomolecular tools thanks to their prominent advantages. Diversity of spatial structures, ease of production through chemical synthesis and a large variety of chemical modifications make aptamers convenient building blocks for the generation of multifunctional constructs. An opportunity to combine different aptamer functionalities with other molecules of interest such as reporter groups, nanoparticles, chemotherapeutic agents, siRNA or antisense oligonucleotides provides a widest range of applications of multivalent aptamers. The present review summarizes approaches to the design of multivalent aptamers, various examples of multifunctional constructs and the prospects of employing them as components of biosensors, probes for affinity capture, tools for cell research and potential therapeutic candidates. Full article

(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)

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