Académie royale de Médecine de Belgique

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Résumé de Toshio Miyata (Séance du 20 mai 2006)

STRUCTURE BASED DRUG DESIGN FOR NOVEL INHIBITORS OF SERINE PROTEASE INHIBITOR (SERPIN) 

par T. MIYATA (Tokai University School of Medicine – Japon), correspondant étranger.

Serine protease inhibitors (serpin) not only play a central role in various pathological processes including coagulation, fibrinolysis,malignancy and inflammation, but may also occasionally polymerize within cells and produce abnormalities recently identified as serpinopathies.  Serpins consist of a β-sheet rich body with a reactive loop, whose insertion into the strand four positions (s4A) of the A β-sheet triggers the serpin’s biological activity and may also, in some circumstances, initiate a serpinopathy. Inhibition of serpins may prove therapeutic.  As yet, however, only very few small molecule serpin inhibitors have been reported.  We therefore apply for the first time a new approach, the structure based drug design, to identify novel, orally active small molecule serpin inhibitors.  We choose plasminogen activator inhibitor (PAI-1), a clinically important serpin, whose crystal structure has been described, and identify novel, orally active molecules able to enter into the s4A position as a mock compound.  In vitro they specifically inhibit the PAI-1 activity and enhance fibrinolysis activity.  In vivo they efficiently inhibit coagulation and bleomycin-induced lung fibrosis without any adverse effect.  Our methodology proves to be a useful tool to obtain effective inhibitors of serpin activity or abnormal conformational change once their three-dimensional structure is elucidated.    

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