G-Quadruplexes with Tetra(ethylene glycol)-Modified Deoxythymidines are Resistant to Nucleases and Inhibit HIV-1 Reverse Transcriptase

G‐quadruplex formation in virally encoded templates arrests reverse transcription. Methods to stabilize this structure are promising for antiviral approaches. To stabilize G‐quadruplex formation, deoxythymidines were modified with tetra(ethylene glycol) (TEG). The TEG‐modified G‐quadruplexes were stabilized significantly relative to unmodified DNA. In the presence of a TEG‐modified oligonucleotide that is capable of forming an intermolecular G‐quadruplex with a template containing a hu‐ man immunodeficiency virus‐1 sequence, reverse transcription was inhibited by more than 70 % relative to the reaction in the absence of the TEG‐modified oligonucleotide. Moreover, the TEG‐modified deoxythymidines protected the DNA oligonucleotide from degradation by various nucleases in human serum. Thus, DNA oligonucleotides modified with TEG have potential in therapeutic applications. A G‐triplex‐forming oligonucleotide containing a region complementary to the HIV‐1 genome formed an intermolecular G‐quadruplex with its target. When the G‐triplex region was modified with tetra(ethylene glycol) (TEG), HIV‐1 reverse transcriptase was inhibited by more than 70 %. The TEG modification also protected the oligonucleotide from degradation by nucleases in human serum.