The Experts below are selected from a list of 684 Experts worldwide ranked by ideXlab platform
Piet Herdewijn - One of the best experts on this subject based on the ideXlab platform.
-
structure activity relationship study of a potent α thrombin binding aptamer incorporating Hexitol nucleotides
Chemistry: A European Journal, 2020Co-Authors: Maria De Fenza, Piet Herdewijn, Elena Eremeeva, Romualdo Troisi, Hui Yang, Anna Esposito, Filomena Sica, Daniele Dalonzo, Annalisa GuaragnaAbstract:The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with Hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single Hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the Hexitol backbone. Importantly, the NU172-TH 9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of Hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.
-
highly stable Hexitol based xna aptamers targeting the vascular endothelial growth factor
Nucleic Acids Research, 2019Co-Authors: Elena Eremeeva, Mikhail Abramov, Antonios Fikatas, Lia Margamuljana, Dominique Schols, Elisabetta Groaz, Piet HerdewijnAbstract:Biomedical applications of nucleic acid aptamers are limited by their rapid degradation in biological fluids and generally demand tedious post-selection modifications that might compromise binding. One possible solution to warrant biostability is to directly evolve chemically modified aptamers from xenobiotic nucleic acids (XNAs). We have isolated fully modified 2'-O-methyl-ribose-1,5-anhydroHexitol nucleic acid (MeORNA-HNA) aptamers targeting the rat vascular endothelial growth factor 164 (rVEGF164). Three sequences have been identified that interact with the target protein with affinities in the low-nanomolar range and HNA modifications appeared to be mandatory for their tight binding. The evolution of these XNA aptamers was accomplished using an in vitro selection procedure starting from a fully sugar-modified library containing a 20mer 2'-OMe-ribonucleotide region followed by a 47mer HNA sequence. The high binding affinity and selectivity of the selected aptamers were confirmed by several methods including gel-shift, fluorescence polarisation, and enzyme-linked oligonucleotide assays. The isolated HNA ligands exhibited higher specificity to the rVEGF164 and human VEGF165 isoforms compared to rat VEGF120, while very low binding efficiencies were observed to streptavidin and thrombin. Furthermore, it was clearly demonstrated that the resulting aptamers possessed a superior stability to degradation in human serum and DNase I solutions.
-
synthesis of 3 fluoro 4 amino Hexitol nucleosides with a pyrimidine nucleobase as building blocks for oligonucleotides
Tetrahedron, 2019Co-Authors: Amit M. Jabgunde, Eveline Lescrinier, Rahul S. Patil, Steven De Jonghe, Leonid Beigelman, Piet HerdewijnAbstract:Abstract The synthesis of 3′-fluoro-4′-amino-Hexitol nucleosides with a uracil and cytosine nucleobase was performed. The synthesis started from 1,5:2,3-dianhydro-4,6-benzylidene-allitol and afforded the target compounds in 15 steps. These protected Hexitol nucleosides are valuable building blocks for the preparation of a new class of oligonucleotides.
-
Synthesis of Protected Amino Hexitol Nucleosides as Building Blocks for Oligonucleotide Synthesis
2018Co-Authors: Amit M. Jabgunde, Rahul S. Patil, Steven De Jonghe, Leonid Beigelman, Piet HerdewijnAbstract:A new synthesis protocol for the preparation of hitherto unknown 1′,5′-anhydro-4′-amino-trityl/MMTr Hexitol nucleosides has been developed. Key steps in the synthesis of the pyrimidine analogues (U and C) include the regioselective d-allo-Hexitol oxirane and 2′,4′-anhydronucleoside ring opening by uracil and azide, respectively. A different strategy using a regioselective epoxide ring opening of d-gulo-oxirane, followed by a SN2 type of azidation reaction, has been adopted for the purine analogues (A and G). These compounds can be easily converted to 6′-phosphoramidites for the solid-phase synthesis of N4′ → P6′ phosphoramidates of amino Hexitol nucleic acids (AHNA)
-
1′,5′-Anhydro‑l-ribo-Hexitol Adenine Nucleic Acids (α‑l‑HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World
2015Co-Authors: Daniele D’alonzo, Guy Schepers, Arthur Van Aerschot, Piet Herdewijn, Giovanni Palumbo, Mathy Froeyen, Giovanni Di Fabio, Annalisa GuaragnaAbstract:The synthesis and a preliminary investigation of the base pairing properties of (6′ → 4′)-linked 1′,5′-anhydro-l-ribo-Hexitol nucleic acids (α-l-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the “all equatorial” pyranyl sugar backbone, α-l-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-l-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids
Arthur Van Aerschot - One of the best experts on this subject based on the ideXlab platform.
-
1′,5′-Anhydro‑l-ribo-Hexitol Adenine Nucleic Acids (α‑l‑HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World
2015Co-Authors: Daniele D’alonzo, Guy Schepers, Arthur Van Aerschot, Piet Herdewijn, Giovanni Palumbo, Mathy Froeyen, Giovanni Di Fabio, Annalisa GuaragnaAbstract:The synthesis and a preliminary investigation of the base pairing properties of (6′ → 4′)-linked 1′,5′-anhydro-l-ribo-Hexitol nucleic acids (α-l-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the “all equatorial” pyranyl sugar backbone, α-l-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-l-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids
-
synthesis and base pairing properties of 1 5 anhydro l Hexitol nucleic acids l hna
Chemistry: A European Journal, 2009Co-Authors: Daniele Dalonzo, Guy Schepers, Arthur Van Aerschot, Annalisa Guaragna, Jef Rozenski, Giovanni Palumbo, Stefania Capone, Piet HerdewijnAbstract:Oligonucleotides composed of 1',5'-anhydro-arabino-Hexitol nucleosides belonging to the L series ( L -HNA) were prepared and preliminarily studied as a novel potential base-pairing system. Synthesis of enantiopure L -Hexitol nucleotide monomers equipped with a 2'-(N 6 -benzoyladenin-9-yl) or a 2'-(thymin-1-yl) moiety was carried out by a de novo approach based on a domino reaction as key step. The L oligonucleotide analogues were evaluated in duplex formation with natural complements as well as with unnatural sugar-modified oligonucleotides. In many cases stable homo- and hetero-chiral associations were found. Besides T m measurements, detection of hetero-chiral complexes was unambiguously confirmed by LC-MS studies. Interestingly, circular dichroism measurements of the most stable duplexes suggested that L -HNA form left-handed helices with both D and L oligonucleotides.
-
biological effects of Hexitol and altritol modified sirnas targeting b raf
European Journal of Pharmacology, 2009Co-Authors: Michael Fisher, Arthur Van Aerschot, Mikhail Abramov, Jef Rozenski, Vidula Dixit, R L Juliano, Piet HerdewijnAbstract:Increasing the effectiveness of siRNAs through chemical modification is an important task. Here we describe altritol and Hexitol modified oligonucleotides targeting the B-Raf oncogene that is critical for the growth and survival of melanoma cells. Using assays for apoptosis, DNA synthesis, colony formation and B-Raf protein and message levels, we demonstrate that certain Hexitol modifications can improve the effectiveness of B-Raf siRNAs and also increase duration of action. Altritol modified siRNAs were similar to or slightly less effective than unmodified B-Raf siRNA. Modifications at the 3' or 5' end of the sense strand, at the 3' end of the antisense strand, or within either strand were well tolerated. The basis for the increased effectiveness of the Hexitol-modified siRNAs is not fully understood but may be partly due to increased stability to nucleases.
-
Synthesis and evaluation of Hexitol nucleoside congeners as ambiguous nucleosides
Tetrahedron Letters, 2007Co-Authors: Catia Lambertucci, Guy Schepers, Piet Herdewijn, Gloria Cristalli, Arthur Van AerschotAbstract:Abstract A series of anhydroHexitol nucleoside congeners was synthesized as ambiguous or so-called universal nucleosides and was evaluated for their hybridization potential and discrimination properties. The 1,5-anhydro-2,3-dideoxy-2-(5-nitroindazol-1-yl)- d -arabino-Hexitol 4e showed the lower spread in Tm values upon hybridization to the natural bases, with minimal destabilization, and therefore behaved as a true ambiguous nucleoside.
-
Replication of Hexitol oligonucleotides as a prelude to the propagation of a third type of nucleic acid in vivo.
Comptes Rendus Biologies, 2003Co-Authors: Sylvie Pochet, Piet Herdewijn, Arthur Van Aerschot, Pierre Alexandre Kaminski, Philippe MarlièreAbstract:No backbone motif other than phospho-ribose and phospho-deoxyribose has been found in natural nucleic acids, currently restricting the molecular types of replicable biopolymers to DNA and RNA. With the aim of propagating and expressing a third type of nucleic acid in vivo, we assessed the replicability of polynucleotides with a phospho-Hexitol backbone (HNA) in vivo and in vitro. Faithful polymerisation of up to four deoxynucleotides templated by Hexitol oligonucleotides was established in vitro using DNA polymerase from Escherichia coli (PolA Klenow exo-fragment) and Thermus aquaticus (Taq polymerase). Condensation of up to three successive hTTPs (Hexitol thymidine triphosphate) in responses to a pentameric Hexitol template (hA)5 could also be demonstrated in vitro. Such a marginal HNA-dependent HNA polymerase activity of natural polymerases may be evolved in the future to catalyse in vitro amplification of HNA. The transmission of a two-codon-long genetic message carried on a hexameric Hexitol template was also established using a selection screen for restoring thymidylate synthase activity in E. coli. These results exemplify the potential that can be explored by converting artificial substrates with natural enzymes in the field of informational polymer synthesis.
Herdewijn Piet - One of the best experts on this subject based on the ideXlab platform.
-
Structure-Activity Relationship Study of a Potent alpha-Thrombin Binding Aptamer Incorporating Hexitol Nucleotides
'Wiley', 2020Co-Authors: De Fenza Maria, Eremeeva Elena, Troisi Romualdo, Yang Hui, Esposito Anna, Sica Filomena, Herdewijn Piet, D'alonzo Daniele, Guaragna AnnalisaAbstract:The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with Hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single Hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the Hexitol backbone. Importantly, the NU172-TH 9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of Hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.status: publishe
-
Synthesis of 3 '-fluoro-4 '-amino-Hexitol nucleosides with a pyrimidine nucleobase as building blocks for oligonucleotides
'Elsevier BV', 2019Co-Authors: Jabgunde, Amit M, Lescrinier Eveline, De Swarup, De Jonghe Steven, Patil, Rahul S, Beigelman Leonid, Herdewijn PietAbstract:© 2019 Elsevier Ltd The synthesis of 3′-fluoro-4′-amino-Hexitol nucleosides with a uracil and cytosine nucleobase was performed. The synthesis started from 1,5:2,3-dianhydro-4,6-benzylidene-allitol and afforded the target compounds in 15 steps. These protected Hexitol nucleosides are valuable building blocks for the preparation of a new class of oligonucleotides.status: publishe
-
Highly stable Hexitol based XNA aptamers targeting the vascular endothelial growth factor
'Oxford University Press (OUP)', 2019Co-Authors: Eremeeva Elena, Abramov Mikhail, Fikatas Antonios, Margamuljana Lia, Schols Dominique, Groaz Elisabetta, Herdewijn PietAbstract:Biomedical applications of nucleic acid aptamers are limited by their rapid degradation in biological fluids and generally demand tedious post-selection modifications that might compromise binding. One possible solution to warrant biostability is to directly evolve chemically modified aptamers from xenobiotic nucleic acids (XNAs). We have isolated fully modified 2'-O-methyl-ribose-1,5-anhydroHexitol nucleic acid (MeORNA-HNA) aptamers targeting the rat vascular endothelial growth factor 164 (rVEGF164). Three sequences have been identified that interact with the target protein with affinities in the low-nanomolar range and HNA modifications appeared to be mandatory for their tight binding. The evolution of these XNA aptamers was accomplished using an in vitro selection procedure starting from a fully sugar-modified library containing a 20mer 2'-OMe-ribonucleotide region followed by a 47mer HNA sequence. The high binding affinity and selectivity of the selected aptamers were confirmed by several methods including gel-shift, fluorescence polarisation, and enzyme-linked oligonucleotide assays. The isolated HNA ligands exhibited higher specificity to the rVEGF164 and human VEGF165 isoforms compared to rat VEGF120, while very low binding efficiencies were observed to streptavidin and thrombin. Furthermore, it was clearly demonstrated that the resulting aptamers possessed a superior stability to degradation in human serum and DNase I solutions.status: publishe
-
Synthesis of Protected Amino Hexitol Nucleosides as Building Blocks for Oligonucleotide Synthesis
'American Chemical Society (ACS)', 2018Co-Authors: De Swarup, Jabgunde, Amit M, Pati, Rahul S, De Jonghe Steven, Beigelrnan Leonid, Herdewijn PietAbstract:A new synthesis protocol for the preparation of hitherto unknown 1',5'-anhydro-4'-amino-trityl/MMTr Hexitol nucleosides has been developed. Key steps in the synthesis of the pyrimidine analogues (U and C) include the regioselective d- allo-Hexitol oxirane and 2',4'-anhydronucleoside ring opening by uracil and azide, respectively. A different strategy using a regioselective epoxide ring opening of d- gulo-oxirane, followed by a SN2 type of azidation reaction, has been adopted for the purine analogues (A and G). These compounds can be easily converted to 6'-phosphoramidites for the solid-phase synthesis of N4' → P6' phosphoramidates of amino Hexitol nucleic acids (AHNA).status: publishe
-
1',5'-Anhydro-l-ribo-Hexitol Adenine Nucleic Acids (α-l-HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World
American Chemical Society, 2015Co-Authors: D'alonzo Daniele, Herdewijn Piet, Schepers Guy, Van Aerschot Arthur, Palumbo Giovanni, Froeyen Mathy, Di Fabio Giovanni, Guaragna AnnalisaAbstract:The synthesis and a preliminary investigation of the base pairing properties of (6' → 4')-linked 1',5'-anhydro-l-ribo-Hexitol nucleic acids (α-l-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the "all equatorial" pyranyl sugar backbone, α-l-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-l-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids.status: publishe
Leslie E Orgel - One of the best experts on this subject based on the ideXlab platform.
-
nonenzymatic synthesis of rna and dna oligomers on Hexitol nucleic acid templates the importance of the a structure
Journal of the American Chemical Society, 1999Co-Authors: Igor A Kozlov, Arthur Van Aerschot, Piet Herdewijn, Roger Busson, Panagiotis K Politis, Leslie E OrgelAbstract:Hexitol nucleic acid (HNA) is an analogue of DNA containing the standard nucleoside bases, but with a phosphorylated 1,5-anhydroHexitol backbone. HNA oligomers form duplexes having the nucleic acid A structure with complementary DNA or RNA oligomers. The HNA decacytidylate oligomer is an efficient template for the oligomerization of the 5'-phosphoroimidazolides of guanosine or deoxyguanosine. Comparison of the oligomerization efficiencies on HNA, RNA, and DNA decacytidylate templates under various conditions suggests strongly that only nucleic acid double helices with the A structure support efficient template-directed synthesis when 5'-phosphoroimidazolides of nucleosides are used as substrates.
-
efficient transfer of information from Hexitol nucleic acids to rna during nonenzymatic oligomerization
Journal of the American Chemical Society, 1999Co-Authors: Igor A Kozlov, Piet Herdewijn, A Van Aerschot, B De Bouvere, Leslie E OrgelAbstract:Hexitol nucleic acids (HNAs) are DNA analogues that contain the standard nucleoside bases attached to a phosphorylated 1,5-anhydroHexitol backbone. We find that HNAs support efficient information transfer in nonensymatic template-directed reactions. HNA heterosequences appeared to be superior to the corresponding DNA heterosequences in facilitating synthesis of complementary oligonucleotides from nucleoside-5'-phosphoro-2-methyl imidazolides.
-
a highly enantio selective Hexitol nucleic acid template for nonenzymatic oligoguanylate synthesis
Journal of the American Chemical Society, 1999Co-Authors: Igor A Kozlov, Piet Herdewijn, Panagiotis K Politis, Stefan Pitsch, Leslie E OrgelAbstract:The authors compare the enantiomeric cross-inhibition of D- and L-guanosine 5'-phosphoro-2-methyl-imidazole (I) polymn. on C10 (RNA), dC10 (DNA), or hC10 (Hexitol nucleic acid) (II). RNA or DNA templates catalyze efficient oligomerization of D-I, with a strong enantiomeric cross-inhibition by L-I, but II shows efficient oligomerization of D-I with a less sever cross-inhibition, resulting in G6-9 polymers, thus showing that efficient selection of one optical isomer from a racemic mixt. of nucleotides during nonenzymic oligo-nucleotide synthesis on an analog of a nucleic acid template is possible, which may be of relevance to prebiotic conditions. [on SciFinder (R)]
Annalisa Guaragna - One of the best experts on this subject based on the ideXlab platform.
-
structure activity relationship study of a potent α thrombin binding aptamer incorporating Hexitol nucleotides
Chemistry: A European Journal, 2020Co-Authors: Maria De Fenza, Piet Herdewijn, Elena Eremeeva, Romualdo Troisi, Hui Yang, Anna Esposito, Filomena Sica, Daniele Dalonzo, Annalisa GuaragnaAbstract:The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with Hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single Hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the Hexitol backbone. Importantly, the NU172-TH 9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of Hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.
-
1′,5′-Anhydro‑l-ribo-Hexitol Adenine Nucleic Acids (α‑l‑HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World
2015Co-Authors: Daniele D’alonzo, Guy Schepers, Arthur Van Aerschot, Piet Herdewijn, Giovanni Palumbo, Mathy Froeyen, Giovanni Di Fabio, Annalisa GuaragnaAbstract:The synthesis and a preliminary investigation of the base pairing properties of (6′ → 4′)-linked 1′,5′-anhydro-l-ribo-Hexitol nucleic acids (α-l-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the “all equatorial” pyranyl sugar backbone, α-l-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-l-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids
-
synthesis and base pairing properties of 1 5 anhydro l Hexitol nucleic acids l hna
Chemistry: A European Journal, 2009Co-Authors: Daniele Dalonzo, Guy Schepers, Arthur Van Aerschot, Annalisa Guaragna, Jef Rozenski, Giovanni Palumbo, Stefania Capone, Piet HerdewijnAbstract:Oligonucleotides composed of 1',5'-anhydro-arabino-Hexitol nucleosides belonging to the L series ( L -HNA) were prepared and preliminarily studied as a novel potential base-pairing system. Synthesis of enantiopure L -Hexitol nucleotide monomers equipped with a 2'-(N 6 -benzoyladenin-9-yl) or a 2'-(thymin-1-yl) moiety was carried out by a de novo approach based on a domino reaction as key step. The L oligonucleotide analogues were evaluated in duplex formation with natural complements as well as with unnatural sugar-modified oligonucleotides. In many cases stable homo- and hetero-chiral associations were found. Besides T m measurements, detection of hetero-chiral complexes was unambiguously confirmed by LC-MS studies. Interestingly, circular dichroism measurements of the most stable duplexes suggested that L -HNA form left-handed helices with both D and L oligonucleotides.