Replacing thymine with a strongly pairing fifth Base: A combined quantum mechanics and molecular dynamics study

Chawla, Mohit; Gorle, Suresh; Shaikh, Abdul Rajjak; Oliva, Romina; Cavallo, Luigi

doi:10.1016/j.csbj.2021.02.006

Cited by 15 publications

(17 citation statements)

References 86 publications

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“…For example, the activated form of 2‐thiouridine has been found to have favorable properties for copying RNA sequences, [29,30] and so do 3′‐amino‐2′,3′‐dideoxynucleotides with 2‐thiothymidine as base [31,32] . Recent studies on hybridization probes showed that ethynylpyridone C ‐nucleosides can pair even more strongly and selectively than 2‐thiothymidine [33] does with adenine in DNA target strands, [34,35] and the pairing is confirmed in theoretical studies [36,37] . Further, an ethynylpyridone analog of azidothymidine (AZT) has recently shown detectable antiviral activity [38] .…”

Section: Figurementioning

confidence: 83%

“…[ 31 , 32 ] Recent studies on hybridization probes showed that ethynylpyridone C ‐nucleosides can pair even more strongly and selectively than 2‐thiothymidine [33] does with adenine in DNA target strands,[ 34 , 35 ] and the pairing is confirmed in theoretical studies. [ 36 , 37 ] Further, an ethynylpyridone analog of azidothymidine (AZT) has recently shown detectable antiviral activity. [38] This prompted us to ask whether nucleotide monomers with the ethynylpyridone base would be successfully incorporated in primer extension assays.…”

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confidence: 99%

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High Fidelity Enzyme‐Free Primer Extension with an Ethynylpyridone Thymidine Analog

Han

Kervio

Richert

2021

Chemistry A European J

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High fidelity base pairing is important for the transmission of genetic information. Weak base pairs can lower fidelity, complicating sequencing, amplification and replication of DNA. Thymidine 5'-monophosphate (TMP) is the most weakly pairing nucleotide among the canonical deoxynucleotides, causing high errors rates in enzyme-free primer extension. Here we report the synthesis of an ethynylpyridone C-nucleoside analog of 3'-amino-2',3'dideoxythymidine monophosphate and its incorporation in a growing strand by enzyme-free primer extension. The ethynylpyridone C-nucleotide accelerates extension more than five-fold, reduces misincorporation and readily displaces TMP in competition experiments. The results bode well for the use of the C-nucleoside as replacements for thymidine in practical applications.

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Section: Figurementioning

confidence: 83%

mentioning

confidence: 99%

High Fidelity Enzyme‐Free Primer Extension with an Ethynylpyridone Thymidine Analog

Han

Kervio

Richert

2021

Chemistry A European J

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“…Molecular dynamics (MD) simulations have been proven to be very useful and effective method in order to study the stability and analysis of biological systems (60). In fact, our research group has successfully utilized and employed MD simulations to check the stability of different protein complexes (61)(62)(63) and nucleic acid systems (64)(65)(66)(67). In this study, we used the GROMACS (45) software for molecular dynamics simulation to understand the structural properties and interaction between TLR-5 and the predicted multi-epitope vaccine.…”

Section: Simulations Predicts a Stable Tlr-5 And Multi-epitope Vaccin...mentioning

confidence: 99%

Immunoinformatics Aided Design and In-Vivo Validation of a Cross-Reactive Peptide Based Multi-Epitope Vaccine Targeting Multiple Serotypes of Dengue Virus

Kaushik

Gupta

et al. 2022

Front. Immunol.

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Dengue virus (DENV) is an arboviral disease affecting more than 400 million people annually. Only a single vaccine formulation is available commercially and many others are still under clinical trials. Despite all the efforts in vaccine designing, the improvement in vaccine formulation against DENV is very much needed. In this study, we used a roboust immunoinformatics approach, targeting all the four serotypes of DENV to design a multi-epitope vaccine. A total of 13501 MHC II binding CD4+ epitope peptides were predicted from polyprotein sequences of four dengue virus serotypes. Among them, ten conserved epitope peptides that were interferon-inducing were selected and found to be conserved among all the four dengue serotypes. The vaccine was formulated using antigenic, non-toxic and conserved multi epitopes discovered in the in-silico study. Further, the molecular docking and molecular dynamics predicted stable interactions between predicted vaccine and immune receptor, TLR-5. Finally, one of the mapped epitope peptides was synthesized for the validation of antigenicity and antibody production ability where the in-vivo tests on rabbit model was conducted. Our in-vivo analysis clearly indicate that the imunogen designed in this study could stimulate the production of antibodies which further suggest that the vaccine designed possesses good immunogenicity.

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“…In this context, C ‐nucleosides have recently come into focus as surrogates with increased affinity for adenine in target strands. In particular, ethynylpyridones have shown potential to overcome the poor target affinity and fidelity of thymine or uracil [10–14] …”

Section: Introductionmentioning

confidence: 99%

“…In particular, ethynylpyridones have shown potential to over-come the poor target affinity and fidelity of thymine or uracil. [10][11][12][13][14] While several methods for setting up the C-nucleoside framework are known, [15,16] the incorporation in oligonucleotides usually relied on phosphoramidite or H-phosphonate-based coupling [10] on controlled pore glass as solid support as the predominant method. In automated syntheses, phosphoramidites are the preferred building blocks for chain assembly.…”

Section: Introductionmentioning

confidence: 99%

Acid‐Stable Nucleobase Protection for a Strongly Pairing Pyridone C‐Nucleoside Suitable for Solid‐Phase Synthesis of Oligonucleotides

et al. 2022

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Oligonucleotides are indispensable tools in diagnostics, therapeutic applications and molecular biology. The low base pairing strength of thymine with adenine complicates their use. Ethynylpyridone C-nucleosides are analogs of thymidine that pair more strongly and with improved base selectivity, and sequences containing these analogs show improved target affinity and selectivity, but their routine use is hampered by diminished yields of solid-phase syntheses with the known building blocks. A partial loss of base protecting groups during the acidic deblocking step of chain extension cycles was identified as the cause of lower yields. Here we report the synthesis of an improved phosphoramidite building block featuring a pivaloyloxymethyl (POM) base protecting group. This building block gives oligonucleotides containing the strongly pairing ethynylmethylpyridone C-nucleoside in high yield and purity via solid-phase synthesis.

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Replacing thymine with a strongly pairing fifth Base: A combined quantum mechanics and molecular dynamics study

Abstract: Graphical abstract

Cited by 15 publications

References 86 publications

High Fidelity Enzyme‐Free Primer Extension with an Ethynylpyridone Thymidine Analog

High Fidelity Enzyme‐Free Primer Extension with an Ethynylpyridone Thymidine Analog

Immunoinformatics Aided Design and In-Vivo Validation of a Cross-Reactive Peptide Based Multi-Epitope Vaccine Targeting Multiple Serotypes of Dengue Virus

Acid‐Stable Nucleobase Protection for a Strongly Pairing Pyridone C‐Nucleoside Suitable for Solid‐Phase Synthesis of Oligonucleotides

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