| Abstract
| - Original inhibitors of HIV-1 protease based on a chiral bicyclic guanidinium scaffold linked toshort peptidic mimics of the terminal protease sequences and to a lipophilic group were designed.These inhibitors prevent dimerization of the native protease by an interfacial structure at thehighly conserved antiparallel β-strand involving both the N and C termini that substantiallyaccount for dimerization. The preorganized guanidinium spacer introduces additional electrostatic hydrogen-bonding interactions with the C-terminal Phe-99 carboxylate. Lipophilicresidues linked to side chains and the guanidinium scaffold are essential for dimerizationinhibition as ascertained by Zhang kinetics (4, Kid = 290 nM; 6 or 6‘, Kid = 150 nM; 8, Kid =400 nM) combined with a circular dichroism study on the enzyme thermal stability. Remarkably,less hydrophobic compounds result in mixed dimerization (1a and 3) or active site inhibitors(5). Removal of the guanidinium hydrophobic groups leads to less active or inactive ligands.
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