Anti-HIV activity of steric block oligonucleotides.
The unabated increase in spread of HIV infection worldwide has redoubled efforts to discover novel antiviral and virucidal agents that might be starting points for clinical development. Oligonucleotides and their analogs targeted to form complementary duplexes with highly conserved regions of the HIV RNA have shown significant antiviral activity, but to date clinical studies have been dominated by RNase H-inducing oligonucleotide analog phosphorothioates (GEM 91 and 92) that have specificity and efficacy limitations. However, they have proven the principle that oligonucleotides can be safe anti-HIV drugs. Newer oligonucleotide analogs are now available, which act as strong steric block agents of HIV RNA function. We describe our ongoing studies targeting the HIV-1 trans-activation responsive region (TAR) and the viral packaging signal (psi) with steric block oligonucleotides of varying chemistry and demonstrate their great potential for steric blocking of viral protein interactions in vitro and in cells and describe the first antiviral studies. Peptide nucleic acids (PNA) disulfide linked to cell-penetrating peptides (CPP) have been found to have particular promise for the lipid-free direct delivery into cultured cells and are excellent candidates for their development as antiviral and virucidal agents.
Ivanova
Gabriela
G
Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.
Arzumanov
Andrey A
AA
Turner
John J
JJ
Reigadas
Sandrine
S
Toulmé
Jean-Jacques
JJ
Brown
Douglas E
DE
Lever
Andrew M L
AM
Gait
Michael J
MJ
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D006678:HIV / Q000235:genetics; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D006801:Humans; D009841:Oligonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D020135:Peptide Nucleic Acids / Q000627:therapeutic use; D012367:RNA, Viral / Q000187:drug effects
D019380:Anti-HIV Agents; D009841:Oligonucleotides; D020135:Peptide Nucleic Acids; D012367:RNA, Viral