IADR Abstract Archives

Oleoyl-Galardins, Bi-headed Proteases Inhibitors, as Therapeutic Agents against Periodontal Diseases

Objectives: Unrestrained proteolytic activity constitutes the hallmark of inflammatory response as periodontal diseases. Proteases involved belong mainly to the serine- and metallo-peptidase families. Elevated levels of serine proteases as leukocyte elastase (HLE) and plasmin together with several metalloproteinases (MMPs) including collagenases i.e. MMP-1, MMP-13, gelatinases i.e. MMP-2, MMP-9, and stromelysins i.e. MMP-3, can be identified in periodontal diseases. Serine proteases are the major inducers of proMMP activation creating a local environment with excess of matrix proteolytic activity. Inhibitory substances that can disrupt this degradation cascade may be considered as an effective therapy against periodontal diseases. 

Methods: Long chain unsaturated fatty acids, as oleic acid was reported to interfere with the activity of enzyme systems. Thus, we modified galardin®, a broad spectrum MMP inhibitor, at P’2 position with oleic acid and studied the properties of these derivatives, OL-GAL (CONHOH) or its carboxylic acid counter part, OL-GAL (COOH) by molecular modeling, using specific quenched fluorescent substrates, electrophoreses and cell culture models.

Results: The interactions between oleic acid and HLE, plasmin or MMP-2, involved in the inhibitory capacity of fatty acid towards those proteases were analyzed. For example, the carboxylic acid group of the fatty acid was found to form a salt bridge with Arg217 of HLE. In second, OL-GALs were found less potent MMP inhibitors as compared to galardin® with no selectivity for MMP-2 or MMP-9. Docking computations indicated that contrary to oleic acid, OL-GAL binds only to MMP-2 active site and hydroxamic acid was unable to chelate Zn. Interestingly, oleic acid and particularly OL-GALs proved to potently inhibit MMP-13. These derivatives, as oleic acid, have the capacity to inhibit the amidolytic activity of HLE and plasmin as well as to decrease HLE- and plasmin-mediated proMMP-3 activation.

Conclusions: They might be of therapeutic value in inflammatory disorders as periodontitis.

Pan European Region Meeting
2012 Pan European Region Meeting (Helisinki, Finland)
Helisinki, Finland
2012
82
Scientific Groups
  • Lorimier, Sandrine  ( Unity CNRS FRE3481, Reims, N/A, France )
  • Bourguet, Erika  ( Unity CNRS UMR-7312, Reims, N/A, France )
  • Moroy, Gautier  ( INSERM UMR-S973, Paris, N/A, France )
  • Brassart-pasco, Sylvie  ( Unity CNRS FRE3481, Reims, N/A, France )
  • Alix, Alain Jp  ( Unity CNRS UMR-7312, Reims, N/A, France )
  • Decarme, Martine  ( Unity CNRS FRE3481, Reims, N/A, France )
  • Sapi, Janos  ( Unity CNRS UMR-7312, Reims, N/A, France )
  • Hornebeck, William  ( Unity CNRS FRE3481, Reims, N/A, France )
    • Oral Session
    Pharmacology/Therapeutics/Toxicology
    09/13/2012