Kinetics of G-quartet-mediated tetramer formation.
The phosphorothioate and phosphodiester oligodeoxynucleotides d(TTGGGGTT) form parallel-stranded tetramer structures stabilized by guanosine quartets. The phosphorothioate tetramer has been shown to inhibit human immunodeficiency virus (HIV) in vitro. The kinetics of association and dissociation of both tetramers have been determined as a function of temperature using size exclusion chromatography to measure the ratio of single strand to tetramer. In phosphate buffered saline (pH 7.2) at 37 degrees C, the fourth-order association rate of the phosphorothioate tetramer was 6.1 (+/- 0.5) x 10(4) M-3 s-1; the dissociation rate was 8.2 (+/- 0.2) x 10(-6) min-1, resulting in a t(1/2) of about 60 days. The association rate of the phosphodiester was about one order of magnitude faster and the dissociation rate about one order of magnitude slower than that of the phosphorothioate tetramer. The association reaction had a negative energy of activation for both compounds. Despite thermodynamic instability of the tetramer at low concentrations, the extremely slow dissociation rate may allow use of the phosphorothioate tetramer for AIDS chemotherapy.
Wyatt
J R
JR
ISIS Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
Davis
P W
PW
Freier
S M
SM
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D002850:Chromatography, Gel; D002942:Circular Dichroism; D004355:Drug Stability; D006147:Guanine; D006678:HIV / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013873:Thionucleotides
D000998:Antiviral Agents; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D006147:Guanine