The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Frank Seela - One of the best experts on this subject based on the ideXlab platform.
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5 aza 7 deazaguanine Isoguanine and guanine Isoguanine base pairs in watson crick dna the impact of purine tracts clickable dendritic side chains and pyrene adducts
Chemistry: A European Journal, 2021Co-Authors: Aigui Zhang, Frank Seela, Dasharath Kondhare, Peter LeonardAbstract:The Watson-Crick coding system depends on the molecular recognition of complementary purine and pyrimidine bases. Now, the construction of hybrid DNAs with Watson-Crick and purine-purine base pairs decorated with dendritic side chains was performed. Oligonucleotides with single and multiple incorporations of 5-aza-7-deaza-2'-deoxyguanosine, its tripropargylamine derivative, and 2'-deoxyisoguanosine were synthesized. Duplex stability decreased if single modified purine-purine base pairs were inserted, but increased if pyrene residues were introduced by click chemistry. A growing number of consecutive 5-aza-7-deazaguanine-Isoguanine base pairs led to strong stepwise duplex stabilization, a phenomenon not observed for the guanine-Isoguanine base pair. Spacious residues are well accommodated in the large groove of purine-purine DNA tracts. Changes to the global helical structure monitored by circular dichroism spectroscopy show the impact of functionalization to the global double-helix structure. This study explores new areas of molecular recognition realized by purine base pairs that are complementary in hydrogen bonding, but not in size, relative to canonical pairs.
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parallel stranded dna stabilized with internal sugar cross links synthesis and click ligation of oligonucleotides containing 2 propargylated isoguanosine
ChemInform, 2013Co-Authors: Suresh S Pujari, Frank SeelaAbstract:Internal sugar cross-links were introduced for the first time into oligonucleotides with parallel chain orientation by click ligation. For this, the 2'- or 3'-position of the isoguanosine ribose moiety was functionalized with clickable propargyl residues, and the synthesis of propargylated cytosine building blocks was significantly improved. Phosphoramidites were prepared and employed in solid-phase synthesis. A series of oligo-2'-deoxyribonucleotides with parallel (ps) and antiparallel (aps) strand orientation were constructed containing Isoguanine-cytosine, Isoguanine-isocytosine, and adenine-thymine base pairs. Complementary oligonucleotides with propargylated sugar residues were ligated in a stepwise manner with a chelating bis-azide under copper catalysis. Cross-links were introduced within a base pair or in positions separated by two base pairs. From T(m) stability studies it is evident that cross-linking stabilizes DNA with parallel strand orientation strongly (ΔT(m) from +16 to +18.5 °C) with a similar increase as for aps DNA.
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Parallel Stranded DNA Stabilized with Internal Sugar Cross-Links: Synthesis and Click Ligation of Oligonucleotides Containing 2′‑Propargylated Isoguanosine
2013Co-Authors: Suresh S. Pujari, Frank SeelaAbstract:Internal sugar cross-links were introduced for the first time into oligonucleotides with parallel chain orientation by click ligation. For this, the 2′- or 3′-position of the isoguanosine ribose moiety was functionalized with clickable propargyl residues, and the synthesis of propargylated cytosine building blocks was significantly improved. Phosphoramidites were prepared and employed in solid-phase synthesis. A series of oligo-2′-deoxyribonucleotides with parallel (ps) and antiparallel (aps) strand orientation were constructed containing Isoguanine-cytosine, Isoguanine-isocytosine, and adenine-thymine base pairs. Complementary oligonucleotides with propargylated sugar residues were ligated in a stepwise manner with a chelating bis-azide under copper catalysis. Cross-links were introduced within a base pair or in positions separated by two base pairs. From Tm stability studies it is evident that cross-linking stabilizes DNA with parallel strand orientation strongly (ΔTm from +16 to +18.5 °C) with a similar increase as for aps DNA
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ph independent triplex formation hairpin dna containing Isoguanine or 9 deaza 9 propynylguanine in place of protonated cytosine
Organic and Biomolecular Chemistry, 2006Co-Authors: Frank Seela, Khalil I ShaikhAbstract:Triplex-forming oligonucleotides (TFOs) containing 2′-deoxyisoguanosine (1), 7-bromo-7-deaza-2′-deoxyisoguanosine (2) as well as the propynylated 9-deazaguanine N7-(2′-deoxyribonucleoside) 3b were prepared. For this the phosphoramidites 9a, b of the nucleoside 1 and, the phosphoramidites 19, 20 of compound 3b were synthesized. They were employed in solid-phase oligonucleotide synthesis to yield the protected 31-mer oligonucleotides. The deblocking of the allyl-protected oligonucleotides containing 1 was carried out by Pd(0)[PPh3]4–PPh3 followed by 25% aq. NH3. Formation of the 31-mer single-stranded intramolecular triplexes was studied by UV-melting curve analysis. In the single-stranded 31-mer oligonucleotides the protonated dC in the dCH+–dG–dC base triad was replaced by 2′-deoxyisoguanosine (1), 7-bromo-7-deaza-2′-deoxyisoguanosine (2) and, 9-deaza-9-propynylguanine N7-(2′-deoxyribonucleoside) (3b). The replacement of protonated dC by compounds 1 and 3b resulted in intramolecular triplexes which are formed pH-independently and are stable under neutral conditions. These triplexes contain “purine” nucleosides in the third pyrimidine rich strand of the oligonucleotide hairpin.
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oligonucleotides incorporating n7 2 deoxy β d erythro pentofuranosyl Isoguanine
Nucleosides Nucleotides & Nucleic Acids, 2003Co-Authors: Peter Leonard, Rita Kroschel, Frank SeelaAbstract:Abstract The H-phosphonate and the phosphoramidite of N7-2′-deoxyisoguanosine (2) were prepared and incorporated into oligonucleotide duplexes. Their base pairing properties were investigated and compared with those of the parent purine nucleosides.
Christopher Switzer - One of the best experts on this subject based on the ideXlab platform.
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a dna tetraplex composed of two continuously hydrogen bonded helical arrays of Isoguanine isog
Chemical Physics Letters, 2021Co-Authors: Christopher SwitzerAbstract:Abstract A DNA tetraplex, (isoG4)4-(K+)2-(Na+)12, has been studied at the BP86-D3(BJ)/def2-SVP level employing CPCM with water as solvent. The resulting optimized structure was found to contain two continuously hydrogen-bonded helical arrays of eight isoG nucleobases each. This structure is novel in the domain of oligonucleotide tetramerization, and could help further define molecular recognition by a classical nucleobase first reported by Fischer.
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probing structure and function with alternative nucleic acids bearing 2 5 linked zwitterionic and isocytosine Isoguanine components
Methods, 2001Co-Authors: Christopher Switzer, John C ChaputAbstract:Abstract The incorporation of alternative functional components into nucleic acids can provide insight into what molecular features are necessary for an informational macromolecule to be successful. It can also provide a means to improve particular physical characteristics of nucleic acids for diagnostic and therapeutic purposes, or probe mechanisms. By testing the fitness of nucleic acid-like molecules derived by structural permutations of RNA, it may also prove possible to trace a path from simple prebiotic precursors to biotic molecules. This article describes the applications of 2′,5′-phosphodiester linked, zwitterionic, and base-permuted nucleic acid derivatives.
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reca protein promotes strand exchange with dna substrates containing Isoguanine and 5 methyl isocytosine
Biochemistry, 2000Co-Authors: Kevin P Rice, John C Chaput, Michael M Cox, Christopher SwitzerAbstract:The Escherichia coli RecA protein pairs homologous DNA molecules and promotes DNA strand exchange in vitro. We have examined DNA strand exchange between a 70 nucleotide ssDNA fragment and a 40 bp duplex, in which all G and C residues (at 18 positions distributed throughout the 40 bp exchanged region) were replaced with the nonstandard nucleosides 2‘-deoxyisoguanosine (iG) and 2‘-deoxy-5-methylisocytidine (MiC), respectively. We demonstrate that the nonstandard oligonucleotides are substrates for the RecA protein, permitting DNA strand exchange in vitro at a rate and efficiency comparable to exchange with normal DNA substrates. This observation provides an expanded experimental basis for discussions of potential roles for iG and MiC in a genetic code. Experiments of this type also provide another avenue for exploring RecA-facilitated DNA pairing mechanisms.
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2 deoxyisoguanosine adopts more than one tautomer to form base pairs with thymidine observed by high resolution crystal structure analysis
Biochemistry, 1998Co-Authors: Howard Robinson, Yigui Gao, Cornelia Bauer, Christopher J Roberts, Christopher Switzer, Andrew H J WangAbstract:The questions of whether different tautomeric forms of nucleic acid bases exist to any significant extent in DNA, or what their possible roles in mutation may be, are under intense scrutiny. 2‘-Deoxyisoguanosine (iG) has been suggested to have a propensity to adopt the enol form. Isoguanine (also called 2-hydroxyadenine) can be found in oxidatively damaged DNA generated from treating DNA with a Fenton-type reactive oxygen-generating system and is known to cause mutation. We have analyzed the three-dimensional structure of the DNA dodecamer d(CGC[iG]AATTTGCG) (denoted iG-DODE) by X-ray crystallography and NMR. The crystal structure of the iG-DODE complexed with the minor groove binder Hoechst 33342, refined to 1.4 A resolution, showed that the two independent iG·T base pairs in the dodecamer duplex adopt different (one in Watson−Crick and the other in wobble) conformations. The high-resolution nature of the structure also affords unprecedented clear information about the conformation and interactions of th...
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theoretical and experimental study of Isoguanine and isocytosine base pairing in an expanded genetic system
Journal of the American Chemical Society, 1997Co-Authors: Christopher C Roberts, And Rajanikanth Bandaru, Christopher SwitzerAbstract:The stabilities of all possible purine/pyrimidine pairings between the isomeric nucleobases isocytosine (iso-C) and Isoguanine (iso-G) and standard genomic bases are reported for two independent oligonucleotide duplexes. Additionally, results are given from ab initio calculations performed on iso-C and iso-G. The calculations are used as an aid in the interpretation of thermodynamic data obtained from duplex denaturation studies. The unnatural iso-C/iso-G pair is found to be as stable as a C/G Watson−Crick pair in both duplex systems. The next most stable unnatural pair is that formed by C/iso-G and is observed to be isoenergetic with a U/A Watson−Crick pair. Ab initio data suggest iso-G may adopt an unprecedented imino oxo tautomer which could explain the unusual stability of the C/iso-G pair. The stability of the other possible unnatural pairs are reported and similarly interpreted in terms of ab initio and other available experimental data. Finally, the fitness is discussed of a six-component genetic s...
Blas Pastor, José Ramón - One of the best experts on this subject based on the ideXlab platform.
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Dinámica de sistemas de interés biológico. Estudios de flexibilidad y estabilidad en sistemas de puente de hidrógeno.
'Edicions de la Universitat de Barcelona', 2006Co-Authors: Blas Pastor, José RamónAbstract:Las interacciones por puente de hidrógeno resultan cruciales en la definición de numerosos procesos de relevancia biológica. Su reconocida importancia como elementos moduladores de la estructura de macromoléculas, su papel en el reconocimiento molecular de especies químicas (iones, fármacos,.), o su actuación en los mecanismos catalíticos de enzimas, resultan ejemplos evidentes de ello.Numerosas metodologías experimentales aportan descripciones muy valiosas del comportamiento de los sistemas modulados por puente de hidrógeno. Junto a ellas, los métodos teóricos constituyen un complemento necesario de cara a obtener una descripción detallada de los aspectos estructurales, energéticos y dinámicos de estos sistemas, así como para simular condiciones de entorno y situaciones químicas concretas que no resultan de fácil acceso a la metodología experimental.La presente tesis se ha centrado en la descripción desde una perspectiva teórica de una serie de sistemas de interés biológico cuyas propiedades vienen determinadas en alto grado por la presencia de puentes de hidrógeno. Los estudios realizados pueden estructurarse en tres bloques temáticos.En un primer bloque, se analiza el papel que desempeña la interacción por puente de hidrógeno como elemento clave en la modulación del reconocimiento selectivo de especies aniónicas por receptores orgánicos. En este punto, nuestro interés está orientado esencialmente a determinar por un lado la estructura del complejo de interacción entre el receptor y el anión, así como la estabilidad relativa de dicha interacción frente a diversos aniones. Por otra parte, un objetivo complementario consiste en detrminar la flexibilidad intrínseca del receptor orgánico, con el fin de determinar el posible coste conformacional asociado a la reorganización de su estructura como paso previo al reconocimiento del anión.En un segundo bloque, se estudia el comportamiento dinámico de los ácidos nucleicos, cuya estructura, estabilidad y flexibilidad viene determinado en parte por la presencia de interacciones de puente de hidrógeno. A su vez, dichas interacciones son claves en el mantenimiento del código genético, así como en la posibilidad de poder reconocer la secuencia de bases a lo largo de los surcos del DNA, lo cual subyace en el reconocimiento selectivo frente a pequeños ligandos o proteínas. En particular, nuestro interés se orienta al estudio de la flexibilidad conformacional del dúplex de DNA mediante una serie de herramientas teóricas que permitan extraer información directa acerca de su naturaleza dinámica.Finalmente, en un tercer bloque se examina el efecto que tiene el mantenimiento de las pautas de puente de hidrógeno en la conservación del código genético y en el funcionamiento de aplicaciones biotecnológicas basadas en ácidos nucleicos sintéticos. Así, nuestro objetivo se orienta en eset caso hacia la comprensión de las propiedades mutagénicas de la isoguanina, que está estrechamente relacionadas con su enorme versatilidad tautomérica, que le permite definir distintos patrones de interacción basada en puentes de hidrógeno. Asimismo, también ha sido nuestro objetivo examinar las características químicas de nucleobases expandidas, basadas en la modificación de las bases naturales mediante inserción o adición de un anillo de benzeno, como paso previo al estudio de su posible utilización como elementos estructurales en el diseño de dúplexes modificados de potencial valor biotecnológico.Hydrogen bond interactions are crucial elements in the definition of many processes of biological relevance. Their recognized importance as modulators of macromolecular structure, their role in molecular recognition between chemical species (ions, drugs,.), or their action in catalytic enzymatic mechanisms, are clear examples of this.Numerous experimental methodologies bring valuable descriptions of hydrogen bond modulated systems. Furthermore, theoretical models act as a necessary complement in order to obtain more accurate explanations of structural, energetic and dynamic aspects of these systems, as well as to simulate environmental conditions and chemical situations which are not easily accessible to experimental approaches.Present dissertation has focused on the description, from a theoretical point of view, of a series of systems of biological interest which properties are to a high extent determined by the presence of hydrogen bond interactions. Studies performed can be exposed in three thematic blocks.In a first section, the role played by hydrogen bond interactions in modulating the selective recognition of anions by organic receptors is analyzed. In this point, our interest by one hand is essentially driven to determine the structure of the interaction complex between receptor and anion, as well as the relative stability of this interaction towards several anions. In the other hand, a complementary objective is to determine the intrinsic flexibility of the organic receptor, so as to evaluate the possible conformational cost associated to its structural reorganization previous to anion recognition.In a second part, we study the dynamic behavior of nucleic acids, the structure, stability and flexibility of which are somehow modulated by the presence of hydrogen bond interactions. Besides, these interactions are crucial for the maintenance of genetic code, and for the ability of recognizing base sequence along DNA grooves, which underlies in the selective recognition of this biomolecule by small ligands or proteins. In particular, our interest is oriented towards the study of conformational flexibility of DNA duplexes by using a wide set of theoretical tools which allow to extract direct information about its dynamic nature.Finally, in a third section, we study the effect of maintaining hydrogen bond patterns in the conservation of the genetic code and in the performance of biotechnological applications based on synthetic nucleic acids. In this way, our objective is oriented towards the understanding of mutagenic properties of Isoguanine, which are closely related to its enormous tautomeric versatility, which allows it to define alternative interaction patterns based on hydrogen bond. Moreover, it has also been our objective to examine the chemical features of expanded nucleobases, consisting in the modification of natural bases by the addition or insertion of a benzene ring, as a previous step to study its possible use as structural elements in the design of modified duplexes of biotechnological interest
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Dinámica de sistemas de interés biológico. Estudios de flexibilidad y estabilidad en sistemas de puente de hidrógeno.
'Edicions de la Universitat de Barcelona', 2006Co-Authors: Blas Pastor, José RamónAbstract:[spa] Las interacciones por puente de hidrógeno resultan cruciales en la definición de numerosos procesos de relevancia biológica. Su reconocida importancia como elementos moduladores de la estructura de macromoléculas, su papel en el reconocimiento molecular de especies químicas (iones, fármacos,.), o su actuación en los mecanismos catalíticos de enzimas, resultan ejemplos evidentes de ello. Numerosas metodologías experimentales aportan descripciones muy valiosas del comportamiento de los sistemas modulados por puente de hidrógeno. Junto a ellas, los métodos teóricos constituyen un complemento necesario de cara a obtener una descripción detallada de los aspectos estructurales, energéticos y dinámicos de estos sistemas, así como para simular condiciones de entorno y situaciones químicas concretas que no resultan de fácil acceso a la metodología experimental. La presente tesis se ha centrado en la descripción desde una perspectiva teórica de una serie de sistemas de interés biológico cuyas propiedades vienen determinadas en alto grado por la presencia de puentes de hidrógeno. Los estudios realizados pueden estructurarse en tres bloques temáticos. En un primer bloque, se analiza el papel que desempeña la interacción por puente de hidrógeno como elemento clave en la modulación del reconocimiento selectivo de especies aniónicas por receptores orgánicos. En este punto, nuestro interés está orientado esencialmente a determinar por un lado la estructura del complejo de interacción entre el receptor y el anión, así como la estabilidad relativa de dicha interacción frente a diversos aniones. Por otra parte, un objetivo complementario consiste en detrminar la flexibilidad intrínseca del receptor orgánico, con el fin de determinar el posible coste conformacional asociado a la reorganización de su estructura como paso previo al reconocimiento del anión. En un segundo bloque, se estudia el comportamiento dinámico de los ácidos nucleicos, cuya estructura, estabilidad y flexibilidad viene determinado en parte por la presencia de interacciones de puente de hidrógeno. A su vez, dichas interacciones son claves en el mantenimiento del código genético, así como en la posibilidad de poder reconocer la secuencia de bases a lo largo de los surcos del DNA, lo cual subyace en el reconocimiento selectivo frente a pequeños ligandos o proteínas. En particular, nuestro interés se orienta al estudio de la flexibilidad conformacional del dúplex de DNA mediante una serie de herramientas teóricas que permitan extraer información directa acerca de su naturaleza dinámica. Finalmente, en un tercer bloque se examina el efecto que tiene el mantenimiento de las pautas de puente de hidrógeno en la conservación del código genético y en el funcionamiento de aplicaciones biotecnológicas basadas en ácidos nucleicos sintéticos. Así, nuestro objetivo se orienta en eset caso hacia la comprensión de las propiedades mutagénicas de la isoguanina, que está estrechamente relacionadas con su enorme versatilidad tautomérica, que le permite definir distintos patrones de interacción basada en puentes de hidrógeno. Asimismo, también ha sido nuestro objetivo examinar las características químicas de nucleobases expandidas, basadas en la modificación de las bases naturales mediante inserción o adición de un anillo de benzeno, como paso previo al estudio de su posible utilización como elementos estructurales en el diseño de dúplexes modificados de potencial valor biotecnológico.[eng] Hydrogen bond interactions are crucial elements in the definition of many processes of biological relevance. Their recognized importance as modulators of macromolecular structure, their role in molecular recognition between chemical species (ions, drugs,.), or their action in catalytic enzymatic mechanisms, are clear examples of this. Numerous experimental methodologies bring valuable descriptions of hydrogen bond modulated systems. Furthermore, theoretical models act as a necessary complement in order to obtain more accurate explanations of structural, energetic and dynamic aspects of these systems, as well as to simulate environmental conditions and chemical situations which are not easily accessible to experimental approaches. Present dissertation has focused on the description, from a theoretical point of view, of a series of systems of biological interest which properties are to a high extent determined by the presence of hydrogen bond interactions. Studies performed can be exposed in three thematic blocks. In a first section, the role played by hydrogen bond interactions in modulating the selective recognition of anions by organic receptors is analyzed. In this point, our interest by one hand is essentially driven to determine the structure of the interaction complex between receptor and anion, as well as the relative stability of this interaction towards several anions. In the other hand, a complementary objective is to determine the intrinsic flexibility of the organic receptor, so as to evaluate the possible conformational cost associated to its structural reorganization previous to anion recognition. In a second part, we study the dynamic behavior of nucleic acids, the structure, stability and flexibility of which are somehow modulated by the presence of hydrogen bond interactions. Besides, these interactions are crucial for the maintenance of genetic code, and for the ability of recognizing base sequence along DNA grooves, which underlies in the selective recognition of this biomolecule by small ligands or proteins. In particular, our interest is oriented towards the study of conformational flexibility of DNA duplexes by using a wide set of theoretical tools which allow to extract direct information about its dynamic nature. Finally, in a third section, we study the effect of maintaining hydrogen bond patterns in the conservation of the genetic code and in the performance of biotechnological applications based on synthetic nucleic acids. In this way, our objective is oriented towards the understanding of mutagenic properties of Isoguanine, which are closely related to its enormous tautomeric versatility, which allows it to define alternative interaction patterns based on hydrogen bond. Moreover, it has also been our objective to examine the chemical features of expanded nucleobases, consisting in the modification of natural bases by the addition or insertion of a benzene ring, as a previous step to study its possible use as structural elements in the design of modified duplexes of biotechnological interest
Anna Pasternak - One of the best experts on this subject based on the ideXlab platform.
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novel Isoguanine derivative of unlocked nucleic acid investigations of thermodynamics and biological potential of modified thrombin binding aptamer
PLOS ONE, 2018Co-Authors: Weronika Kotkowiak, Tomasz Czapik, Anna PasternakAbstract:Thrombin binding aptamer (TBA), is a short DNA 15-mer that forms G-quadruplex structure and possesses anticoagulant properties. Some chemical modifications, including unlocked nucleic acids (UNA), 2'-deoxy-isoguanosine and 2'-deoxy-4-thiouridine were previously found to enhance the biological activity of TBA. In this paper, we present thermodynamic and biological characteristics of TBA variants that have been modified with novel Isoguanine derivative of UNA as well as isoguanosine. Additionally, UNA-4-thiouracil and 4-thiouridine were also introduced simultaneously with Isoguanine derivatives. Thermodynamic analysis indicates that the presence of isoguanosine in UNA or RNA series significantly decreases the stability of G-quadruplex structure. The highest destabilization is observed for substitution at one of the G-tetrad position. Addition of 4-thiouridine in UNA or RNA series usually decreases the unfavorable energetic cost of the presence of UNA or RNA Isoguanine. Circular dichroism and thermal denaturation spectra in connection with thrombin time assay indicate that the introduction of UNA-Isoguanine or isoguanosine into TBA negatively affects G-quadruplex folding and TBA anticoagulant properties. These findings demonstrate that the highly-ordered structure of TBA is essential for inhibition of thrombin activity.
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Novel Isoguanine derivative of unlocked nucleic acid—Investigations of thermodynamics and biological potential of modified thrombin binding aptamer
2018Co-Authors: Weronika Kotkowiak, Tomasz Czapik, Anna PasternakAbstract:Thrombin binding aptamer (TBA), is a short DNA 15-mer that forms G-quadruplex structure and possesses anticoagulant properties. Some chemical modifications, including unlocked nucleic acids (UNA), 2′-deoxy-isoguanosine and 2′-deoxy-4-thiouridine were previously found to enhance the biological activity of TBA. In this paper, we present thermodynamic and biological characteristics of TBA variants that have been modified with novel Isoguanine derivative of UNA as well as isoguanosine. Additionally, UNA-4-thiouracil and 4-thiouridine were also introduced simultaneously with Isoguanine derivatives. Thermodynamic analysis indicates that the presence of isoguanosine in UNA or RNA series significantly decreases the stability of G-quadruplex structure. The highest destabilization is observed for substitution at one of the G-tetrad position. Addition of 4-thiouridine in UNA or RNA series usually decreases the unfavorable energetic cost of the presence of UNA or RNA Isoguanine. Circular dichroism and thermal denaturation spectra in connection with thrombin time assay indicate that the introduction of UNA-Isoguanine or isoguanosine into TBA negatively affects G-quadruplex folding and TBA anticoagulant properties. These findings demonstrate that the highly-ordered structure of TBA is essential for inhibition of thrombin activity.
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Novel Isoguanine derivative of unlocked nucleic acid—Investigations of thermodynamics and biological potential of modified thrombin binding aptamer - Fig 1
2018Co-Authors: Weronika Kotkowiak, Tomasz Czapik, Anna PasternakAbstract:Structure of thrombin binding aptamer (A) and novel Isoguanine derivative of UNA (B).
Weronika Kotkowiak - One of the best experts on this subject based on the ideXlab platform.
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novel Isoguanine derivative of unlocked nucleic acid investigations of thermodynamics and biological potential of modified thrombin binding aptamer
PLOS ONE, 2018Co-Authors: Weronika Kotkowiak, Tomasz Czapik, Anna PasternakAbstract:Thrombin binding aptamer (TBA), is a short DNA 15-mer that forms G-quadruplex structure and possesses anticoagulant properties. Some chemical modifications, including unlocked nucleic acids (UNA), 2'-deoxy-isoguanosine and 2'-deoxy-4-thiouridine were previously found to enhance the biological activity of TBA. In this paper, we present thermodynamic and biological characteristics of TBA variants that have been modified with novel Isoguanine derivative of UNA as well as isoguanosine. Additionally, UNA-4-thiouracil and 4-thiouridine were also introduced simultaneously with Isoguanine derivatives. Thermodynamic analysis indicates that the presence of isoguanosine in UNA or RNA series significantly decreases the stability of G-quadruplex structure. The highest destabilization is observed for substitution at one of the G-tetrad position. Addition of 4-thiouridine in UNA or RNA series usually decreases the unfavorable energetic cost of the presence of UNA or RNA Isoguanine. Circular dichroism and thermal denaturation spectra in connection with thrombin time assay indicate that the introduction of UNA-Isoguanine or isoguanosine into TBA negatively affects G-quadruplex folding and TBA anticoagulant properties. These findings demonstrate that the highly-ordered structure of TBA is essential for inhibition of thrombin activity.
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Novel Isoguanine derivative of unlocked nucleic acid—Investigations of thermodynamics and biological potential of modified thrombin binding aptamer
2018Co-Authors: Weronika Kotkowiak, Tomasz Czapik, Anna PasternakAbstract:Thrombin binding aptamer (TBA), is a short DNA 15-mer that forms G-quadruplex structure and possesses anticoagulant properties. Some chemical modifications, including unlocked nucleic acids (UNA), 2′-deoxy-isoguanosine and 2′-deoxy-4-thiouridine were previously found to enhance the biological activity of TBA. In this paper, we present thermodynamic and biological characteristics of TBA variants that have been modified with novel Isoguanine derivative of UNA as well as isoguanosine. Additionally, UNA-4-thiouracil and 4-thiouridine were also introduced simultaneously with Isoguanine derivatives. Thermodynamic analysis indicates that the presence of isoguanosine in UNA or RNA series significantly decreases the stability of G-quadruplex structure. The highest destabilization is observed for substitution at one of the G-tetrad position. Addition of 4-thiouridine in UNA or RNA series usually decreases the unfavorable energetic cost of the presence of UNA or RNA Isoguanine. Circular dichroism and thermal denaturation spectra in connection with thrombin time assay indicate that the introduction of UNA-Isoguanine or isoguanosine into TBA negatively affects G-quadruplex folding and TBA anticoagulant properties. These findings demonstrate that the highly-ordered structure of TBA is essential for inhibition of thrombin activity.
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Novel Isoguanine derivative of unlocked nucleic acid—Investigations of thermodynamics and biological potential of modified thrombin binding aptamer - Fig 1
2018Co-Authors: Weronika Kotkowiak, Tomasz Czapik, Anna PasternakAbstract:Structure of thrombin binding aptamer (A) and novel Isoguanine derivative of UNA (B).
