Confocal microscopy studies of a model oligoribonucleotide HIV inhibitor.

Previous work has shown that novel amphipalhic oligo and polyribonucleotides are potent inhibitors of HIV. It was hypothesized that the mechanism(s) of action for these compounds might be inhibition of retroviral reverse transcriptase (RT) and/or viral uptake by cells. A fluorescent oligonucleotide analog was prepared, and confocal microscopy studies were undertaken in order to examine oligonucleotide-cell interactions.

An unusual "senseless" 2',5'-oligoribonucleotide with potent anti-HIV activity.

A new 32-mer 2',5'-oligoribonucleotide of 1-methyl-6-thioinosinic acid (10) has been synthesized. The design of this unique oligoribonucleotide is based on the reported HIV inhibitory activities of both 2',5'-oligonucleotides and the 3',5'-oligoribonucleotides containing the 1-methyl-6-mercaptopurine base. Tm and CD studies of 10 revealed that it has no organized secondary structure, presumably due to the rigidity of the molecule.

Antiviral amphipathic oligo- and polyribonucleotides: analogue development and biological studies.

A series of novel N1 alkylated purine nucleic acids were polymerized either enzymatically or by automated synthesis to further establish the SAR requirements for HIV, RT, and HCMV activity. Out of the series, two constructs, 2'-O-methyl-1-allylinosinic acid phosphorothioate 33-mer (16) and an oligomer incorporating 1-propyl-6-thioinosinic acid residues (20), were found to be highly active under all three assay conditions. SAR studies indicate that sulfur incorporation, high molecular weight, and low steric bulk at N1 all can be important for activity.

"Senseless" antiviral polyribonucleotides: poly (1-propargylinosinic acid).

Previous work has shown that novel amphipathic oligo and polyribonucleotides exhibiting secondary structure in solution are potent inhibitors of HIV and HCMV replication and cytopathicity in tissue culture. It was hypothesized that the mechanism(s) of action for these compounds might be inhibition of retroviral reverse transcriptase (RT) and/or viral uptake by cells. Pursuit of the essential pharmacophore has led to the discovery of poly (1-propargylinosinic acid) (10), an HIV and HCMV-active polyribonucleotide lacking the secondary structure previously thought to be essential for the observed antiviral activity.