Stabilizing contributions of sulfur-modified nucleotides: crystal structure of a DNA duplex with 20-O-[2-(methoxy)ethyl]-2-thiothymidines

Substitution of oxygen atoms by sulfur at various locations in the nucleic acid framework has led to analogs such as the DNA phosphorothioates and 40-thio RNA. The phosphorothioates are excellent mimics of DNA, exhibit increased resistance to nucle-ase degradation compared with the natural counter-part, and have been widely used as first-generation antisensenucleicacidanalogsforapplications invitro and in vivo. The 40-thio RNA analog exhibits signific-antly 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 inter