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).
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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.