Anti-HIV activities and physicochemical properties of phosphorothioate analogues complementary to HIV sequences

Specific Inhibition of Influenza Virus RNA Polymerase and Nucleoprotein Gene Expression by Liposomally Encapsulated Antisense Phosphorothioate Oligonucleotides in MDCK Cells

“…Using this approach, oligonucleotides can serve as potential blockers of transcription or translation through sequence-specific hybridization with targeted genetic segments. Antisense oligonucleotides have potential roles in the treatment of AIDS, cancer, influenza virus, herpes simplex virus and other diseases (Zamecnik & Stephenson, 1978;Zamecnik et al, 1986;Miller et al, 1985;Smith et al, 1986;Matsukura et al, 1987;Zerial et al, 1987;Leiter et al, 1990;Kim et al, 1991Kim et al, , 1993Whitesell et al, 1991;Simons et al, 1992;Skorski et al, 1994). Although viral replication could be inhibited by unmodified oligonucleotides, the problems of nuclease sensitivity and low cellular uptake limit in vivo applications (Hélène & Toulmé, 1990;Erickson & Yzant, 1992).…”

Properties and Anti-Hiv Activity of Hairpin Antisense Oligonucleotides Containing 2′-Methoxynucleosides with Base-Pairing in the Stem Region at the 3′-End

“…These compounds have been used as antisense inhibitors of gene expression in various culture systems, and are considered to be potential therapeutic agents (Stein and Cohen, 1988;Toulrne and Helene, 1988). Antisense oligonucleotide s complementary to viral RNA inhibit viral replication in cells cultured with Rous sarcoma virus (Zamecnik and Stephenson, 1978), human immunodeficie ncy virus (Zamecnik et a/., 1986;Matsukura et a/., 1987;Kim et a/., 1991Kim et a/., , 1993Kim et a/., , 1995, vesicular stomatitis virus (Miller et a/., 1985), herpes simplex virus (Lemaitre, 1987;Smith et a/., 1986;Zerial et a/., 1987) and influenza virus (Letiter et a/., 1990). However, Agrawal and colleagues (Agrawal et et., 1991) and Iverson (Iverson, 1991) have reported that oligonucleotide phosphorothioa tes are degraded by only 15% in plasma, stomach, and heart after 24 h, whereas in the kidney and liver, degradation reaches about 50% within 48 h. Degradation of unmodified and phosphorothioa te ollgodeoxyrlbonucleotides is primarily from the 3'-end.…”

Inhibition of HIV-1 Replication by Chimeric Phosphorothioate Oligodeoxynucleotides Applied in Free Solution

“…One important reason for using phosphorothioate ODNs in antisense studies has been their resistance to nucleolytic degradation compared to unmodified ODNs [15][16][17]. Resistance to the exonuclease activity present in serum and culture medium can be obtained with only a few terminal backbone linkages modified as phosphorothioate [15,[18][19][20] and the antisense potential of such chimeric ODNs targeted against HIV-1 has also been investigated [21][22][23][24][25][26]. Among these studies, target-specific inhibition of HIV-1 tat mRNA has been demonstrated targeting the splice site of tat intron I [23] and to some extent targeting p24 gag [25].…”

“…Among these studies, target-specific inhibition of HIV-1 tat mRNA has been demonstrated targeting the splice site of tat intron I [23] and to some extent targeting p24 gag [25]. In contrast, targeting the region of translation initiation of HIV-1 rev (previously shown to be accessible to sequence-specific inhibition by fully modified ODNs [2,3,10,27,28]), neither sequence-dependent nor non-sequence-dependent inhibition of HIV-1 has been observed [21,22,24].…”

“…In order to test whether the previously observed lack of inhibition by chimeric anti-rev ODNs [21,22,24] has been due to application of too short ODNs (20 mers) or application of ODNs at too low concentration (0.5 ÌM), we performed an experiment examining longer ODNs (28 mers) at higher concentration (5 ÌM). Relevant control ODNs of inverted and scrambled sequences were included in order to assess the sequence specificity of the observed inhibition.…”