Lipopeptides as dimerization inhibitors of HIV-1 protease

In AIDS therapy, attempts have been made to inhibit the virus-encoded enzym es, e.g, HIV-1 protease, using active site-directed inhibitors. This approa ch is questionable, however, due to virus mutations and the high toxicity o f the drugs, An alternative method to inhibit the dimeric HIV protease is t he targeting of the interface region of the protease subunits in order to p revent subunit dimerization and enzyme activity, This approach should be le ss prone to inactivation by mutation, A list of improved 'dimerization inhi bitors' of HIV-1 protease is presented. The main structural features are a short 'interface' peptide segment, including non-natural amino acids, and a n aliphatic N-terminal blocking group. The high inhibitory power of some of the lipopeptides [e.g, palmitoyl-Tyr-Glu-Leu-OH, palmitoyl-Tyr-Glu-(L-thyr onine)-OH, palmitoyl-Tyr-Glu-(L-biphenyl-alanine)-OH] with low nanomolar K- i values in the enzyme test suggests that mimetics with good bio-availabili ty can be derived for AIDS therapy.