Inhibition of an invader cell or virus, without affecting similar metabolic processes in the host, is a major obstacle in human immunodeficiency virus (HIV) drug design. Bis-linked drugs that target the polypurine tract (PPT) sequence of HIV-1 reverse transcriptase (RT) offer exciting possibilities for effective and selective inhibition of HIV. Our strategy is to attack the template/primer substrate-binding step of RT function at the PPT. This is in contrast to other drugs that block chain elongation (AZT or DDI), or disrupt the catalytic site of the enzyme (nevirapine), or prevent processing of RT by HIV protease (protease inhibitors).

X-ray crystallography is the tool used to study the three dimensional structures of DNA/DNA and RNA/DNA analogues of the PPT, and of their complexes with bis-linked tomaymycin-netropsin and tomaymycin-distamycin drugs. Distamycin binds AT base pairs, while tomaymycin binds covalently to guanine. The PPT consists of both adenine and guanine bases. Gel electrophoresis shows that these bis-linked drugs bind the PPT decamer at 1:2 ratio, and crystals of the drug complex diffract to 4.5 Angstrom. The native gel elctrophoresis indicates further purification is necessary. The purification of these complexes and crystallization trials are in progress.