申请人:Manoharan Muthiah
公开号:US20050288244A1
公开(公告)日:2005-12-29
One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one ligand. In certain embodiments, a ligand is bound to only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, both of the oligonucleotide strands of the double-stranded oligonucleotide independently comprise a bound ligand. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. In certain embodiments, a phosphate linkage in one or both of the strands of the oligonucleotide has been replaced with a phosphorothioate or phosphorodithioate linkage. In a preferred embodiment, the ligand is cholesterol or 5β-cholanic acid. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one ligand. In certain embodiments, the oligonucleotide comprises at least one modified sugar moiety. In certain embodiments, a phosphate linkage of the oligonucleotide has been replaced with a phosphorothioate or phosphorodithioate linkage. In a preferred embodiment, the ligand is cholesterol or 5β-cholanic acid. The ligand improves the pharmacokinetic properties of the oligonucleotide.
本发明的一个方面涉及包含至少一个配体的双链寡核苷酸。在某些实施例中,配体仅结合到构成双链寡核苷酸的两个核苷酸链中的一个。在某些实施例中,双链寡核苷酸的两个核苷酸链都独立地包含一个结合的配体。在某些实施例中,核苷酸链包含至少一个修饰的糖基。在某些实施例中,核苷酸链的一个或两个链中的磷酸酯键已被磷硫酸酯或磷二硫酸酯键替代。在一个首选实施例中,配体是胆固醇或5β-胆烷酸。本发明的另一个方面涉及包含至少一个配体的单链寡核苷酸。在某些实施例中,核苷酸包含至少一个修饰的糖基。在某些实施例中,核苷酸的磷酸酯键已被磷硫酸酯或磷二硫酸酯键替代。在一个首选实施例中,配体是胆固醇或5β-胆烷酸。配体改善了寡核苷酸的药代动力学性能。