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.

Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein

“…Data in the present study, however, suggest that monomers lack enzymatic activity, reinforcing the speculation that if a peptide inhibitor were designed to compete with dimer interface sequences, and thereby prevent dimerization, then it might be possible to abate FAP activity in pathologic conditions such as certain neoplasms. 23,37,38 Although our data support that APCE is soluble FAP and that its homodimeric structure appears to be required for activity expression, we also explored whether the enzymes shared substrate specificities. The synthetic substrates, Ala-Pro-AFC and Z-Gly-Pro-AMC, and the FRET peptide, synthesized to contain P4-P4Ј residues of Met-␣ 2 AP (Table 1), were used for kinetic assessments.…”

Scaffolds for Blocking Protein-Protein Interactions

“…The most potent hit, PPBH3-1, bound Bcl-2 with a K d value of 52 ± 5 nM, corresponding to a 100-fold stronger binding affinity in comparison to Bak 72-87 [11]. The authors attributed this enhanced affinity to the rigid, pre-organization of the normally unstructured Bak [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87] binding epitope conferred by the -helix of aPP. Further studies probed the structural requirements for selective binding between the designed peptide motifs and two anti-apoptotic protein analogs, Bcl-2 and Bcl-x L [12].…”

“…The most potent inhibitor from this library of compounds was found to inhibit the dimerization of HIV-1 protease and resulted in a K i value of 80 nM, Fig. (13) [85].…”

Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: A single mode of inhibition for the three HIV enzymes?

“…Bouras et al (1999) introduced a more rigid scaffold in the tether (to increase the conformational constrain), called "molecular tongs" such as resorcinol, 2,6-pyridinediol and 2,7-naphthalenediol, leading compounds active in the micro and submicromalor range. Merabet et al (2004) introduced "new molecular tongs" based on quinoline and naphtalene scaffolds linked to two peptidic strands of different sequence. Some of the compounds prepared acted as dimerization inhibitors at submicromolar concentrations.…”