scholarly journals Locked nucleic acid building blocks as versatile tools for advanced G-quadruplex design

2020 ◽  
Vol 48 (18) ◽  
pp. 10555-10566 ◽  
Author(s):  
Linn Haase ◽  
Klaus Weisz
Keyword(s):  
Nucleic Acid ◽  
Detailed Analysis ◽  
Building Blocks ◽  
Locked Nucleic Acid ◽  
Structural Element ◽  
Hybrid Type ◽  
G Quadruplex ◽  
Conformational Properties ◽  
Neighboring Site ◽  
Potential Use

Abstract A hybrid-type G-quadruplex is modified with LNA (locked nucleic acid) and 2′-F-riboguanosine in various combinations at the two syn positions of its third antiparallel G-tract. LNA substitution in the central tetrad causes a complete rearrangement to either a V-loop or antiparallel structure, depending on further modifications at the 5′-neighboring site. In the two distinct structural contexts, LNA-induced stabilization is most effective compared to modifications with other G surrogates, highlighting a potential use of LNA residues for designing not only parallel but various more complex G4 structures. For instance, the conventional V-loop is a structural element strongly favored by an LNA modification at the V-loop 3′-end in contrast with an alternative V-loop, clearly distinguishable by altered conformational properties and base-backbone interactions as shown in a detailed analysis of V-loop structures.

Development of Strategies for Glycopeptide Synthesis: An Overview on the Glycosidic Linkage

2020 ◽  
Vol 24 (21) ◽  
pp. 2475-2497
Author(s):  
Andrea Verónica Rodríguez-Mayor ◽  
German Jesid Peralta-Camacho ◽  
Karen Johanna Cárdenas-Martínez ◽  
Javier Eduardo García-Castañeda
Keyword(s):  
Chemical Synthesis ◽  
Solid Phase ◽  
Building Blocks ◽  
Heterogeneous Environments ◽  
Phase Synthesis ◽  
Low Concentrations ◽  
Biological Sources ◽  
Synthetic Routes ◽  
The Impact ◽  
Potential Use

Glycoproteins and glycopeptides are an interesting focus of research, because of their potential use as therapeutic agents, since they are related to carbohydrate-carbohydrate, carbohydrate-protein, and carbohydrate-lipid interactions, which are commonly involved in biological processes. It has been established that natural glycoconjugates could be an important source of templates for the design and development of molecules with therapeutic applications. However, isolating large quantities of glycoconjugates from biological sources with the required purity is extremely complex, because these molecules are found in heterogeneous environments and in very low concentrations. As an alternative to solving this problem, the chemical synthesis of glycoconjugates has been developed. In this context, several methods for the synthesis of glycopeptides in solution and/or solid-phase have been reported. In most of these methods, glycosylated amino acid derivatives are used as building blocks for both solution and solid-phase synthesis. The synthetic viability of glycoconjugates is a critical parameter for allowing their use as drugs to mitigate the impact of microbial resistance and/or cancer. However, the chemical synthesis of glycoconjugates is a challenge, because these molecules possess multiple reaction sites and have a very specific stereochemistry. Therefore, it is necessary to design and implement synthetic routes, which may involve various protection schemes but can be stereoselective, environmentally friendly, and high-yielding. This review focuses on glycopeptide synthesis by recapitulating the progress made over the last 15 years.

scholarly journals Thermal Stability Changes in Telomeric G-Quadruplex Structures Due to N6-Methyladenine Modification

Epigenomes ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 5 ◽  
Author(s):  
Ryohei Wada ◽  
Wataru Yoshida
Keyword(s):  
Thermal Stability ◽  
Base Pair ◽  
Genomic Dna ◽  
Biological Functions ◽  
Duplex Structure ◽  
Stacking Interaction ◽  
Hybrid Type ◽  
G Quadruplex ◽  
Melting Analysis ◽  
Thermal Stability Of

N6-methyladenine modification (m6dA) has recently been identified in eukaryote genomic DNA. The methylation destabilizes the duplex structure when the adenine forms a Watson–Crick base pair, whereas the methylation on a terminal unpaired adenine stabilizes the duplex structure by increasing the stacking interaction. In this study, the effects of m6dA modification on the thermal stability of four distinct telomeric G-quadruplex (G4) structures were investigated. The m6dA-modified telomeric oligonucleotide d[AGGG(TTAGGG)3] that forms a basket-type G4 in Na+, d[(TTAGGG)4TT] that forms a hybrid-type G4 in K+ (Form-2), d[AAAGGG(TTAGGG)3AA] that forms a hybrid-type G4 in K+ (Form-1), and d[GGG(TTAGGG)3T] that forms a basket-type G4 with two G-tetrads in K+ (Form-3) were analyzed. Circular dichroism melting analysis demonstrated that (1) A7- and A19-methylation destabilized the basket-type G4 structure that formed in Na+, whereas A13-methylation stabilized the structure; (2) A15-methylation stabilized the Form-2 G4 structure; (3) A15- and A21-methylations stabilized the Form-1 G4 structure; and (4) A12-methylation stabilized the Form-3 G4 structure. These results suggest that m6dA modifications may affect the thermal stability of human telomeric G4 structures in regulating the biological functions.

Trinucleotide Cap Analogue Bearing a Locked Nucleic Acid Moiety: Synthesis, mRNA Modification, and Translation for Therapeutic Applications

2021 ◽  
Author(s):  
Annamalai Senthilvelan ◽  
Tyson Vonderfecht ◽  
Muthian Shanmugasundaram ◽  
Indra Pal ◽  
Jason Potter ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Locked Nucleic Acid ◽  
Acid Moiety ◽  
Therapeutic Applications

scholarly journals Overlapping but distinct: a new model for G-quadruplex biochemical specificity

2021 ◽  
Author(s):  
Martin Volek ◽  
Sofia Kolesnikova ◽  
Katerina Svehlova ◽  
Pavel Srb ◽  
Ráchel Sgallová ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Drug Design ◽  
Solution Structure ◽  
Biochemical Data ◽  
Biological Regulation ◽  
New Model ◽  
G Quadruplex ◽  
Range Of Functions ◽  
Nucleic Acid Structures ◽  
Sequence Requirements

Abstract G-quadruplexes are noncanonical nucleic acid structures formed by stacked guanine tetrads. They are capable of a range of functions and thought to play widespread biological roles. This diversity raises an important question: what determines the biochemical specificity of G-quadruplex structures? The answer is particularly important from the perspective of biological regulation because genomes can contain hundreds of thousands of G-quadruplexes with a range of functions. Here we analyze the specificity of each sequence in a 496-member library of variants of a reference G-quadruplex with respect to five functions. Our analysis shows that the sequence requirements of G-quadruplexes with these functions are different from one another, with some mutations altering biochemical specificity by orders of magnitude. Mutations in tetrads have larger effects than mutations in loops, and changes in specificity are correlated with changes in multimeric state. To complement our biochemical data we determined the solution structure of a monomeric G-quadruplex from the library. The stacked and accessible tetrads rationalize why monomers tend to promote a model peroxidase reaction and generate fluorescence. Our experiments support a model in which the sequence requirements of G-quadruplexes with different functions are overlapping but distinct. This has implications for biological regulation, bioinformatics, and drug design.

scholarly journals Hybrid-Type SELEX for the Selection of Artificial Nucleic Acid Aptamers Exhibiting Cell Internalization Activity

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 888
Author(s):  
Hiro Uemachi ◽  
Yuuya Kasahara ◽  
Keisuke Tanaka ◽  
Takumi Okuda ◽  
Yoshihiro Yoneda ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Surface Protein ◽  
Functional Screening ◽  
Nucleic Acid Aptamers ◽  
Hybrid Type ◽  
Cell Internalization ◽  
Promising Target ◽  
A Cell ◽  
Exponential Enrichment

Nucleic acid aptamers have attracted considerable attention as next-generation pharmaceutical agents and delivery vehicles for small molecule drugs and therapeutic oligonucleotides. Chemical modification is an effective approach for improving the functionality of aptamers. However, the process of selecting appropriately modified aptamers is laborious because of many possible modification patterns. Here, we describe a hybrid-type systematic evolution of ligands by exponential enrichment (SELEX) approach for the generation of the artificial nucleic acid aptamers effective against human TROP2, a cell surface protein identified by drug discovery as a promising target for cancer therapy. Capillary electrophoresis SELEX was used for the pre-screening of multiple modified nucleic acid libraries and enrichment of TROP2 binding aptamers in the first step, followed by functional screening using cell-SELEX in the second step for the generation of cell-internalizing aptamers. One representative aptamer, Tac-B1, had a nanomolar-level affinity to human TROP2 and exhibited elevated capacity for internalization by cells. Because of the growing interest in the application of aptamers for drug delivery, our hybrid selection approach has great potential for the generation of functional artificial nucleic acid aptamers with ideal modification patterns in vitro.

Solution Structure of a Locked Nucleic Acid Modified Quadruplex: Introducing the V4 Folding Topology

2009 ◽  
Vol 121 (17) ◽  
pp. 3145-3149 ◽  
Author(s):  
Jakob T. Nielsen ◽  
Khalil Arar ◽  
Michael Petersen
Keyword(s):  
Nucleic Acid ◽  
Solution Structure ◽  
Locked Nucleic Acid

ALKYLATION, INTERCALATION, AND CONFORMATIONAL PROPERTIES OF NUCLEIC ACID STRUCTURES

1981 ◽  
Vol 367 (1 Quantum Chemi) ◽  
pp. 295-325 ◽  
Author(s):  
D. Malhotra ◽  
R. Pearlstein ◽  
O. Kikuchi ◽  
S. N. Mohammad ◽  
Y. Nakata ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Conformational Properties ◽  
Nucleic Acid Structures
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