Molecular tongs containing amino acid mimetic fragments: new inhibitors of wild-type and mutated HIV-1 protease dimerization.
We have designed, synthesized, and evaluated the inhibitory activity and metabolic stability of new peptidomimetic molecular tongs based on a naphthalene scaffold for inhibiting HIV-1 protease dimerization. Peptidomimetic motifs were inserted into one peptidic strand to make it resistant to proteolysis. The peptidic character of the molecular tongs can be decreased without changing the way they inhibit dimerization. Mutated HIV-1 proteases are also vulnerable to dimerization inhibitors, and the multimutated protease ANAM-11 is twice as sensitive to the inhibitor compared to wild-type protease. Thus, the metabolic stability of antidimeric molecular tongs can be increased without compromising their ability to inhibit wild-type and mutated HIV-1 proteases in vitro.
Bannwarth
Ludovic
L
Université de Paris-Sud XI, IFR 141, Biocis, UMR-CNRS 8076, Faculté de Pharmacie, 5 Rue J. B. Clément, F-92296 Châtenay-Malabry Cedex, France.
Kessler
Albane
A
Pèthe
Stéphanie
S
Collinet
Bruno
B
Merabet
Naïma
N
Boggetto
Nicole
N
Sicsic
Sames
S
Reboud-Ravaux
Michèle
M
Ongeri
Sandrine
S
D000596:Amino Acids / Q000737:chemistry*; D019281:Dimerization; D004355:Drug Stability; D016333:HIV Protease / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006868:Hydrolysis; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009154:Mutation; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry
D000596:Amino Acids; D017320:HIV Protease Inhibitors; D009281:Naphthalenes; D010455:Peptides; D011725:Pyridines; D016333:HIV Protease