Phosphinic peptides
Zinc metalloproteases inhibitors can be obtained by functionalizing small peptides with an X group chelating the zinc ion in the active site of the enzyme (Fig. 1a) or by developing phosphinic inhibitors (Fig. 1b).
Transition state analogues
Phosphinic peptides by their resemblance to the substrate structure in transition state are considered to be transition state analogs.
Schéma 2 : analogie entre la structure d’un substrat à l’état de transition et la structure d’un peptide phosphinique.
Crystallographic structure
Phosphinic inhibitor interacting with a zinc protease, astacin.
Examples of phosphinic inhibitors
MMP-12 selective inhibitor, the RXP470.1
By combinatorial chemistry approaches, our group has matched RXP470.1 compound (Fig. 5), the first potent and selective inhibitor of MMP-12, a zinc metalloprotease expressed by the macrophage in inflammatory conditions.
Schéma 5 : structure de l’inhibiteur RXP470.1 et profil de sélectivité.
Crystal structure of RXP470.1
The high resolution of RXP470 crystallographic structure (1.15 Å, Fig. 6) interacting with the MMP-12 catalytic domain.
Schéma 6 : détails de la structure cristallographique du complexe MMP-12/RXP470.1 illustrant les diverses interactions entre l’inhibiteur et le site actif de la MMP-12.
RXP470.1 and atherosclerosis model
In a murine model of atherosclerosis, the treatment of mice by the RXP470.1 completely blocks plates growth and reduces their ability to break (Fig. 7).
Schéma 7 : l’infusion du RXP470 pendant 4 semaines dans des souris ApoE-/- bloque la croissance des plaques.