scholarly journals Putative Mechanisms Underlying High Inhibitory Activities of Bimodular DNA Aptamers to Thrombin

Biomolecules ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 41 ◽  
Author(s):  
Elena Zavyalova ◽  
Valeriia Legatova ◽  
Rugiya Alieva ◽  
Arthur Zalevsky ◽  
Vadim Tashlitsky ◽  
...  
Keyword(s):  
Complex Formation ◽  
Inhibitory Activity ◽  
Dna Aptamers ◽  
Conformational Heterogeneity ◽  
Chromatographic Techniques ◽  
G Quadruplex ◽  
Inhibitory Activities ◽  
Modular Structures ◽  
Thermodynamic Background

Nucleic acid aptamers are prospective molecular recognizing elements. Similar to antibodies, aptamers are capable of providing specific recognition due to their spatial structure. However, the apparent simplicity of oligonucleotide folding is often elusive, as there is a balance between several conformations and, in some cases, oligomeric structures. This research is focused on establishing a thermodynamic background and the conformational heterogeneity of aptamers taking a series of thrombin DNA aptamers having G-quadruplex and duplex modules as an example. A series of aptamers with similar modular structures was characterized with spectroscopic and chromatographic techniques, providing examples of the conformational homogeneity of aptamers with high inhibitory activity, as well as a mixture of monomeric and oligomeric species for aptamers with low inhibitory activity. Thermodynamic parameters for aptamer unfolding were calculated, and their correlation with aptamer functional activity was found. Detailed analysis of thrombin complexes with G-quadruplex aptamers bound to exosite I revealed the similarity of the interfaces of aptamers with drastically different affinities to thrombin. It could be suggested that there are some events during complex formation that have a larger impact on the affinity than the states of initial and final macromolecules. Possible mechanisms of the complex formation and a role of the duplex module in the association process are discussed.

scholarly journals Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids

2020 ◽  
Vol 61 (8) ◽  
pp. 1203-1220 ◽  
Author(s):  
Yan Q. Chen ◽  
Thomas G. Pottanat ◽  
Robert W. Siegel ◽  
Mariam Ehsani ◽  
Yue-Wei Qian ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Complex Formation ◽  
Inhibitory Activity ◽  
Caloric Intake ◽  
Fat Tissue ◽  
Fed State ◽  
Quantitative Analyses ◽  
Inhibitory Activities

Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.

Module-Activity Relationship of G-quadruplex Based DNA Aptamers for Human Thrombin

2013 ◽  
Vol 20 (38) ◽  
pp. 4836-4843 ◽  
Author(s):  
E. Zavyalova ◽  
A. Golovin ◽  
G. Pavlova ◽  
A. Kopylov
Keyword(s):  
Activity Relationship ◽  
Dna Aptamers ◽  
G Quadruplex ◽  
Human Thrombin ◽  
Relationship Of

Emerging Role of G-quadruplex DNA as Target in Anticancer Therapy

2017 ◽  
Vol 22 (44) ◽  
pp. 6612-6624 ◽  
Author(s):  
Graziella Cimino-Reale ◽  
Nadia Zaffaroni ◽  
Marco Folini
Keyword(s):  
Anticancer Therapy ◽  
Quadruplex Dna ◽  
G Quadruplex

scholarly journals The Functional Role of Loops and Flanking Sequences of G-Quadruplex Aptamer to the Hemagglutinin of Influenza a Virus

2021 ◽  
Vol 22 (5) ◽  
pp. 2409
Author(s):  
Anastasia A. Bizyaeva ◽  
Dmitry A. Bunin ◽  
Valeria L. Moiseenko ◽  
Alexandra S. Gambaryan ◽  
Sonja Balk ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Core Structure ◽  
Dna Aptamer ◽  
Tertiary Structures ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Flanking Sequences ◽  
Related Proteins

Nucleic acid aptamers are generally accepted as promising elements for the specific and high-affinity binding of various biomolecules. It has been shown for a number of aptamers that the complexes with several related proteins may possess a similar affinity. An outstanding example is the G-quadruplex DNA aptamer RHA0385, which binds to the hemagglutinins of various influenza A virus strains. These hemagglutinins have homologous tertiary structures but moderate-to-low amino acid sequence identities. Here, the experiment was inverted, targeting the same protein using a set of related, parallel G-quadruplexes. The 5′- and 3′-flanking sequences of RHA0385 were truncated to yield parallel G-quadruplex with three propeller loops that were 7, 1, and 1 nucleotides in length. Next, a set of minimal, parallel G-quadruplexes with three single-nucleotide loops was tested. These G-quadruplexes were characterized both structurally and functionally. All parallel G-quadruplexes had affinities for both recombinant hemagglutinin and influenza virions. In summary, the parallel G-quadruplex represents a minimal core structure with functional activity that binds influenza A hemagglutinin. The flanking sequences and loops represent additional features that can be used to modulate the affinity. Thus, the RHA0385–hemagglutinin complex serves as an excellent example of the hypothesis of a core structure that is decorated with additional recognizing elements capable of improving the binding properties of the aptamer.

scholarly journals Role of conformational heterogeneity in ligand recognition by viral RNA molecules

2021 ◽  
Author(s):  
Lev Levintov ◽  
Harish Vashisth
Keyword(s):  
Conformational Changes ◽  
Ribonucleic Acid ◽  
Viral Rna ◽  
Ligand Recognition ◽  
Conformational Heterogeneity ◽  
Rna Molecules ◽  
Environmental Stimuli

Ribonucleic acid (RNA) molecules are known to undergo conformational changes in response to various environmental stimuli including temperature, pH, and ligands. In particular, viral RNA molecules are a key example...

scholarly journals Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fariba Peytam ◽  
Ghazaleh Takalloobanafshi ◽  
Toktam Saadattalab ◽  
Maryam Norouzbahari ◽  
Zahra Emamgholipour ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Rat Small Intestine ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Mild Conditions ◽  
Glucosidase Inhibitors ◽  
Inhibitory Activities

AbstractIn an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.

The role of conformational heterogeneity in the excited state dynamics of linked diketopyrrolopyrrole dimers

2021 ◽  
Author(s):  
Siobhan Bradley ◽  
Ming Chi ◽  
Jonathan White ◽  
Christopher R. Hall ◽  
Lars Goerigk ◽  
...  
Keyword(s):  
Excited State ◽  
Conformational Heterogeneity ◽  
Singlet Fission ◽  
Excited State Dynamics

Diketopyrrolopyrrole (DPP) derivatives have been proposed for both singlet fission and energy upconversion as they meet the energetic requirements and exhibit superior photostability compared to many other chromophores. In this...

scholarly journals Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

2021 ◽  
Author(s):  
Amit Ketkar ◽  
Lane Smith ◽  
Callie Johnson ◽  
Alyssa Richey ◽  
Makayla Berry ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mutation Frequency ◽  
Control Sequence ◽  
Wild Type ◽  
Binding Properties ◽  
High Affinity ◽  
G4 Dna ◽  
G Quadruplex ◽  
Forward Mutagenesis

Abstract We previously reported that human Rev1 (hRev1) bound to a parallel-stranded G-quadruplex (G4) from the c-MYC promoter with high affinity. We have extended those results to include other G4 motifs, finding that hRev1 exhibited stronger affinity for parallel-stranded G4 than either anti-parallel or hybrid folds. Amino acids in the αE helix of insert-2 were identified as being important for G4 binding. Mutating E466 and Y470 to alanine selectively perturbed G4 binding affinity. The E466K mutant restored wild-type G4 binding properties. Using a forward mutagenesis assay, we discovered that loss of hRev1 increased G4 mutation frequency >200-fold compared to the control sequence. Base substitutions and deletions occurred around and within the G4 motif. Pyridostatin (PDS) exacerbated this effect, as the mutation frequency increased >700-fold over control and deletions upstream of the G4 site more than doubled. Mutagenic replication of G4 DNA (±PDS) was partially rescued by wild-type and E466K hRev1. The E466A or Y470A mutants failed to suppress the PDS-induced increase in G4 mutation frequency. These findings have implications for the role of insert-2, a motif conserved in vertebrates but not yeast or plants, in Rev1-mediated suppression of mutagenesis during G4 replication.

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