2‘-<i>O</i>-[2-(Methylthio)ethyl]-Modified Oligonucleotide:  An Analogue of 2‘-<i>O</i>-[2-(Methoxy)-ethyl]-Modified Oligonucleotide with Improved Protein Binding Properties and High Binding Affinity to Target RNA

Prakash, Thazha P.; Manoharan, Muthiah; Kawasaki, Andrew M.; Fraser, Allister S.; Lesnik, Elena A.; Sioufi, Namir; Leeds, Janet M.; Teplova, M.; Egli, Martin

doi:10.1021/bi020264t

Cited by 35 publications

(43 citation statements)

References 18 publications

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“…We digested these sequences with SVPD under conditions reported earlier. 24,29 The products of the digestion were analyzed by RP-HPLC and percent intact AON was plotted against time to understand the degradation pattern for all the oligomers (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Enhanced splice correction by 3′, 5′-serinol and 2′-(ω-O-methylserinol) guarded OMe-RNA/DNA mixmers in cells

Kotikam

Arzumanov

Gait

et al. 2013

Artificial DNA: PNA & XNA

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Section: Resultsmentioning

confidence: 99%

Enhanced splice correction by 3′, 5′-serinol and 2′-(ω-O-methylserinol) guarded OMe-RNA/DNA mixmers in cells

Kotikam

Arzumanov

Gait

et al. 2013

Artificial DNA: PNA & XNA

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“…For example, the gauche effect between O4′ and O2′ that drives the sugar conformational equilibrium toward the C3′- endo side is enhanced by the presence of electronegative atoms or groups in the substituent, as recently demonstrated by extensive analyses of the influence of the chemistry of RNA 2′- O -substituents on the stability of duplexes (37,39,42–44). Combining the 2-thio and 2′- O -MOE modifications generates synergistic stereoelectronic effects that are absent, e.g.…”

Section: Discussionmentioning

confidence: 95%

Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 2'-O-[2-(methoxy)ethyl]-2-thiothymidines

Diop-Frimpong

Prakash²,

Rajeev³

et al. 2005

Nucleic Acids Research

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Substitution of oxygen atoms by sulfur at various locations in the nucleic acid framework has led to analogs such as the DNA phosphorothioates and 4′-thio RNA. The phosphorothioates are excellent mimics of DNA, exhibit increased resistance to nuclease degradation compared with the natural counterpart, and have been widely used as first-generation antisense nucleic acid analogs for applications in vitro and in vivo. The 4′-thio RNA analog exhibits significantly enhanced RNA affinity compared with RNA, and shows potential for incorporation into siRNAs. 2-Thiouridine (s2U) and 5-methyl-2-thiouridine (m5s2U) are natural nucleotide analogs. s2U in tRNA confers greater specificity of codon–anticodon interactions by discriminating more strongly between A and G compared with U. 2-Thio modification preorganizes the ribose and 2′-deoxyribose sugars for a C3′-endo conformation, and stabilizes heteroduplexes composed of modified DNA and complementary RNA. Combination of the 2-thio and sugar 2′-O-modifications has been demonstrated to boost both thermodynamic stability and nuclease resistance. Using the 2′-O-[2-(methoxy)ethyl]-2-thiothymidine (m5s2Umoe) analog, we have investigated the consequences of the replacement of the 2-oxygen by sulfur for base-pair geometry and duplex conformation. The crystal structure of the A-form DNA duplex with sequence GCGTAT*ACGC (T* = m5s2Umoe) was determined at high resolution and compared with the structure of the corresponding duplex with T* = m5Umoe. Notable changes as a result of the incorporation of sulfur concern the base-pair parameter ‘opening’, an improvement of stacking in the vicinity of modified nucleotides as measured by base overlap, and a van der Waals interaction between sulfur atoms from adjacent m5s2Umoe residues in the minor groove. The structural data indicate only minor adjustments in the water structure as a result of the presence of sulfur. The observed small structural perturbations combined with the favorable consequences for pairing stability and nuclease resistance (when combined with 2′-O-modification) render 2-thiouracil-modified RNA a promising candidate for applications in RNAi.

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“…The interaction/binding of oligonucleotides to proteins is an important parameter influencing toxicity, plasma half-life, tissue accumulation, cellular uptake, and activity of antisense oligonucleotides (Beltinger et al, 1995;Prakash et al, 2002;Watanabe et al, 2006;Lai et al, 2007aLai et al, , 2007bStein et al, 2009). Since H-bonding to folded protein structures (e.g., OB fold) is important for oligonucleotide-protein binding we can assume that structural and MEP complementarity are determinants for binding/interaction to take place.…”

Section: Discussionmentioning

confidence: 99%

Quantum Mechanical Studies of DNA and LNA

Koch¹,

Shim

Lindow³

et al. 2014

Nucleic Acid Therapeutics

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Quantum mechanical (QM) methodology has been employed to study the structure activity relations of DNA and locked nucleic acid (LNA). The QM calculations provide the basis for construction of molecular structure and electrostatic surface potentials from molecular orbitals. The topologies of the electrostatic potentials were compared among model oligonucleotides, and it was observed that small structural modifications induce global changes in the molecular structure and surface potentials. Since ligand structure and electrostatic potential complementarity with a receptor is a determinant for the bonding pattern between molecules, minor chemical modifications may have profound changes in the interaction profiles of oligonucleotides, possibly leading to changes in pharmacological properties. The QM modeling data can be used to understand earlier observations of antisense oligonucleotide properties, that is, the observation that small structural changes in oligonucleotide composition may lead to dramatic shifts in phenotypes. These observations should be taken into account in future oligonucleotide drug discovery, and by focusing more on non RNA target interactions it should be possible to utilize the exhibited property diversity of oligonucleotides to produce improved antisense drugs.

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2‘-O-[2-(Methylthio)ethyl]-Modified Oligonucleotide: An Analogue of 2‘-O-[2-(Methoxy)-ethyl]-Modified Oligonucleotide with Improved Protein Binding Properties and High Binding Affinity to Target RNA

Cited by 35 publications

References 18 publications

Enhanced splice correction by 3′, 5′-serinol and 2′-(ω-O-methylserinol) guarded OMe-RNA/DNA mixmers in cells

Enhanced splice correction by 3′, 5′-serinol and 2′-(ω-O-methylserinol) guarded OMe-RNA/DNA mixmers in cells

Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 2'-O-[2-(methoxy)ethyl]-2-thiothymidines

Quantum Mechanical Studies of DNA and LNA

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