An alternative strategy for inhibiting multidrug-resistant mutants of the dimeric HIV-1 protease by targeting the subunit interface.
Mutations that occur in response to the HIV-1 protease inhibitors are responsible for the development of multidrug cross-resistance to these antiproteases in AIDS treatment. One alternative to inhibiting the active site of HIV-1 protease is to target the dimer interface of the homodimeric enzyme at the antiparallel beta-sheet formed by the interdigitation of the C- and N-ends of each monomer. This region is highly conserved and is responsible for approx. 75% of the dimer-stabilization energy. The strategies that have been used to design small molecules to target the interface antiparallel beta-sheet have produced lipopeptides, guanidinium derivatives and peptides (or peptidomimetics) cross-linked with spacers. The mechanism of inhibition was determined using a combination of kinetic and biophysical methods. These dimerization inhibitors proved equally active in vitro against both wild-type and mutated proteases. They are therefore promising alternatives to active-site-directed inhibitors in AIDS therapy. Disruption of protein-protein interactions by small molecules is a new way to obtain potentially therapeutic molecules.
Bannwarth
L
L
Enzymologie Moléculaire et Fonctionnelle, FRE 2852, CNRS-Université Paris 6, Institut Jacques Monod, 2 place Jussieu, 75251 Cedex 05, France.
Reboud-Ravaux
M
M
D001665:Binding Sites / Q000235:genetics; D019281:Dimerization; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020836:Protein Structure, Quaternary; D021122:Protein Subunits
D017320:HIV Protease Inhibitors; D021122:Protein Subunits; D016333:HIV Protease