Abstract for Keystone Symposia 2010:

Blocking HIV-1 cell entry has long been a major target in anti-HIV drug development. There are three major steps in HIV cell entry that can be targeted: the gp120-CD4 interaction, the gp120-CCR5 (or CXCR4) interaction, and the gp41 6-helix bundle formation. Inhibitors have been designed for each of these steps.  But blocking only one step is usually not effective enough, and resistant HIV strains emerge to evade the inhibitor. Our aim is to develop a more effective anti-HIV drug, using a combination of entry inhibitors. We carefully selected several inhibitors that target different steps of entry and have been shown to be the most potent in their categories. By testing different ways of combining them, our preliminary results showed that combined inhibitors have similar or even better anti-HIV potency than the individual components. Combined inhibitors also behave better in the presence of competition with non-sense cells, and are more resistant to wash-out, and are thus potentially better suited to physiological conditions. Several of our inhibitors are extremely effective in all tested conditions and have excellent potential as anti-HIV microbicides.