Hybrid oligonucleotides: Synthesis, biophysical properties, stability studies, and biological activity

• Published in: Bioorganic & medicinal chemistry 1996-10, Vol.4 (10), p.1685-1692
• Main Authors: Yu, Dong, Iyer, Radhakrishnan P., Shaw, Denise R., Lisziewicz, Julianna, Li, Ying, Jiang, Zhiwei, Roskey, Allysen, Agrawal, Sudhir
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Complement Hemolytic Activity Assay; Hot Temperature; Nucleic Acid Denaturation; Oligonucleotides - chemical synthesis; Oligonucleotides - chemistry; Ribonuclease H - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(96)00160-5

We have designed and synthesized hybrid oligonucleotides 2–5, as analogues of oligodeoxynucleoside phosphorothioates, in an effort to have agents with improved ‘antisense activity’ with reduced phosphorothioate content. The hybrid oligonucleotides contain segments of 2′- O-methyl ribonucleoside phosphoric diesters and oligodeoxynucleoside phosphorothioates. Thus, compared with the ‘all’ phosphorothioate analogues 1 and 6, the analogues 2–5 showed significantly reduced effect on complement activation. In addition, thermal denaturation studies with complementary RNA revealed that the analogues 2–5 had higher T m compared with that with oligodeoxynucleoside phosphorothioates. Additionally, the RNA component of the oligo/RNA duplex is efficiently cleaved by RNase H, the site of endonucleolytic cleavage being dictated by the length of the oligodeoxynucleoside phosphorothioate segment. Hybrid oligonucleotides containing segments of 2′-OMe ribonucleoside phosphoric diester (PO) segments in a deoxynucleoside phosphorothioate (PS) framework shows improved antisense properties.