Hybrid oligonucleotides: synthesis, biophysical properties, stability studies, and biological activity.
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 Tm 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.
Yu
D
D
Hybridon Inc., Worcester, MA 01605, USA.
Iyer
R P
RP
Shaw
D R
DR
Lisziewicz
J
J
Li
Y
Y
Jiang
Z
Z
Roskey
A
A
Agrawal
S
S
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry*; D015941:Complement Hemolytic Activity Assay; D006358:Hot Temperature; D009691:Nucleic Acid Denaturation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D016914:Ribonuclease H / Q000378:metabolism
D019380:Anti-HIV Agents; D009841:Oligonucleotides; D016914:Ribonuclease H