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Matrixins inhibition and drug design

Objective



Matrix Metalloproteinases (MMPs), also named matrixins, are important targets for drugs to combat diseases as diverse as arthritis, atherosclerosis and cancer. MMPs are indeed of great importance in physiological and pathological tissue degradation. The molecular design of specific inhibitors will lead to therapeutic intervention in these diseases. First generation MMPs inhibitors are already available, but their efficacy and specificity needs to be improved. The overall objective of this transnational proposal is to coordinate various European scientific teams and expertise in chemistry, biochemistry, molecular and cell biology, as well as in cancer invasion and metastasis. The aim is to promote rapid exchange of knowledge, technical expertise, reagents and personnel involving 8 teams from 5 European Countries. It is anticipated that Coordinated European Research on structural biology of MMPs complexed with specific inhibitors and development of biochemical entities with optimised activities will lead to a rapid increase in information about the structure and target specificity of matrixins. This could not be attained by individual activities alone. It will lead to the molecular design of selective MMP inhibitors specific for each enzyme. These inhibitors could be clinically useful drugs for treatment of cancer and other diseases.
Four major measurable objectives are addressed and will be explored together in this Transnational European Programme (for details, see section 7: "Partnership").
1) Production of 6 MMPS and synthetic inhibitors specific for each enzyme, as well as standardization of assay procedures to evaluate the effect of these inhibitors. Our interest will focus on 6 different MMPs that play a key role in cancer invasion and two families of inhibitors (synthetic inhibitors and phosphinic peptides).
2) Experimental determination of the tridimensional structure by X Ray and NMR analysis of complexes of MMP and inhibitor (synthetic inhibitors and phosphinic peptides).
3) Development of biochemical entities displaying optimised MMP-inhibitory activities: drug engineering of improved synthetic inhibitors and selection of appropriate inhibitors based on combinatorial chemistry of phosphinic peptides. Our network is unique in that it has the exclusivity of European expertise in the design of phosphinic peptides.
4) Evaluation of these improved inhibitors in different in-vitro and in-vivo assays of tumor invasion and metastasis.
Many technical and industrial benefits are expected on completion of the proposed project: The design of different synthetic inhibitors and selection of most potent and selective inhibitors of phosphinic peptides libraries of each matrixin will lead to the development of new therapeutic strategies and particularly the development of new anti-cancer drugs. Many synthetic inhibitors with poor selectivity are being developed by pharmaceutical companies. These multi-potent inhibitors are being evaluated in phase II/III clinical trials (Hodgson, Biotechnology 13: 554,1995). Their clinical relevance seems to be hindered by their lack of specificity. Questions therefore become crucial concerning their specificity against each MMP, selectivity and bio-availability. Advances in the design of useful inhibitors will depend on exploiting increased knowledge of the binding sub-sites of the catalytic domain of each matrixin together with the use of combinatorial chemistry of phosphinic peptides.

Coordinator

Université de Liège
Address

4000 Liège
Belgium

Participants (7)

Böhringer Mannheim GmbH
Germany
Address
116,Sandhofer Straße
68305 Mannheim
Centre National de la Recherche Scientifique
France
Address
1,Rue Laurent Fries 1
67404 Illkirch
Commissariat à l'Energie Atomique (CEA)
France
Address
Centre D'etudes De Saclay
91191 Gif-sur-yvette
MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.
Germany
Address
18A,am Klopferspitz 18A
82152 Planegg / Krailling
NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS
Greece
Address
Panepistimiopolis Zographou
15771 Zographos, Athens
Stiftung Deutsches Krebsforschungszentrum
Germany
Address
280,Im Neuenheimer Feld
69120 Heidelberg
University of East Anglia
United Kingdom
Address
University Plain
NR4 7TJ Norwich