Abstract
In AIDS therapy, attempts have been made to inhibit
the virus-encoded enzymes, e.g. HIV-1 protease, using active site-directed
inhibitors. This approach is questionable, however, due to virus mutations and
the high toxicity of the drugs. An alternative method to inhibit the dimeric
HIV protease is the targeting of the interface region of the protease subunits
in order to prevent subunit dimerization and enzyme activity. This approach
should be less prone to inactivation by mutation. A list of improved
‘dimerization inhibitors’ of HIV-1 protease is presented. The main structural
features are a short ‘interface’ peptide segment, including non-natural amino
acids, and an 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-thyronine)-OH, palmitoyl-Tyr-Glu-(L-biphenyl-alanine)-OH] with low
nanomolar Ki valuesin the enzyme test suggests that mimetics with good
bio-availability can be derived for AIDS therapy.
Rapid Synthesis and In Situ Screening of Potent HIV-1 Protease Dimerization Inhibitors