title: New constrained "molecular tongs" designed to dissociate HIV-1 protease dimer.
abstract: New "molecular tongs" based on naphthalene and quinoline scaffolds linked to two peptidic strands were synthesized. They were designed to prevent dimerization of HIV-1 protease by targeting the antiparallel beta-sheet involving N- and C-termini of each monomer. Compared to "molecular tongs" previously described (Bouras, A.; Boggetto, N.; Benatalah, Z.; de Rosny, E.; Sicsic, S.; Reboux-Ravaud, M. J. Med. Chem. 1999, 42, 957-962), two main different structural features were introduced: positively charged quinoline as a new scaffold and two peptidic strands displaying different sequences. Seventeen new "molecular tongs" with dipeptidic or tripeptidic strands were synthesized. These molecules were assayed on HIV-1 protease using the Zhang kinetic technique. Eleven molecules behaved as pure dimerization inhibitors, mostly at the submicromolar range. Compared to a naphthalene scaffold, the quinoline one was shown in several cases to favor dimerization inhibition. The simplified hydrophobic Val-Leu-Val-OMe strand was confirmed as particularly favorable. The C-terminal analogue strand Thr-Leu-Asn-OMe was shown to be the best one for inducing dimerization inhibition (K(id) of 80 nM for compound 30). The mechanism of inhibition was ascertained using ANS binding and gel filtration. Experimental results are in agreement with the dissociation of the HIV-1 protease dimeric form in the presence of the synthesized molecular tongs.
authors.affiliation: Biocis, UMR-CNRS 8076, Faculté de Pharmacie, Université de Paris-Sud, 5 rue J. B. Clément, F-92296 Châtenay-Malabry Cedex, France.
authors.forename: Naïma
authors.initials: N
authors.lastname: Merabet
authors.forename: Julien
authors.initials: J
authors.lastname: Dumond
authors.forename: Bruno
authors.initials: B
authors.lastname: Collinet
authors.forename: Laurence
authors.initials: L
authors.lastname: Van Baelinghem
authors.forename: Nicole
authors.initials: N
authors.lastname: Boggetto
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ongeri
authors.forename: Fariza
authors.initials: F
authors.lastname: Ressad
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Sames
authors.initials: S
authors.lastname: Sicsic
mesh_terms: D019281:Dimerization; D016333:HIV Protease / Q000737:chemistry*; D015497:HIV-1; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D009281:Naphthalenes; D009842:Oligopeptides; D011804:Quinolines; D016333:HIV Protease