High-affinity ssDNA inhibitors of the reverse transcriptase of type 1 human immunodeficiency virus.

The reverse transcriptase (RT) of HIV-1 is a plausible target for therapeutic agents aimed at inhibiting propagation of the virus. We have used "irrational drug design", that is, combinatorial chemistry with oligonucleotide libraries, to identify high-affinity ligands aimed at HIV-1 RT. The methodology, termed SELEX (systematic evolution of ligands by exponential enrichment), was employed with a single-stranded DNA library. The selected ssDNA ligands bind HIV-1 RT with Kd values as low as 1 nM and inhibit the RNA-dependent DNA-polymerase activity of the enzyme with Ki values as low as 0.3 nM. We also demonstrate the high specificity of one ligand able to selectively discriminate between the reverse transcriptases of HIV-1, AMV, and MMLV. These ssDNA molecules may be useful as inhibitors or as models for the design of small molecule inhibitors of HIV-1 RT in vivo.