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Selective fluorinated inhibitors of matrix metalloproteinases 3 and 9

Objective

Heart failure and cancer are the two major causes of death in developed countries. Current therapies for their cure are affected by largely unsolved problems. A common feature of both pathologies is that matrix metalloproteinases (MMPs) 3 and 9, which are zinc-dependent proteolytic enzymes, play a key role. Inhibition of MMPs 3 and 9 is promising for heart failure and cancer therapy, but the currently available inhibitors are poorly selective, and therefore toxic. The primary objective of this project is to discover novel families of inhibitors selective for MMPs 3 and 9 from fluorinated peptidomimetic units. This challenging goal will be pursued by exploiting the potent tools made available by a synergistic and multisciplinary collaboration encompassing all aspects of drug discovery, including fluorine/asymmetric/combinatorial chemistry, structural chemistry, modeling, protein crystallography, pharmacology, physiology and biology, with the additional support of an industrial partner. The other main objective of this research project is to provide an effective training for young scientists at the interface of chemistry and biology in a very competitive international context where discovery of new drugs rests mainly on the ability to use complementary approaches from various disciplines and expertises. Eventually, the scientific achievements stemming from this project will improve our knowledge of a variety of timely and fundamental topics such as
(1) the asymmetric/combinatorial synthesis of chiral fluorinated peptides and mimetics,
(2) the mechanism of action of MMPs,
(3) the behavior of fluorine-containing functions in the enzyme active sites, as well as of their influence on the recognition of the ligand by the enzymes and the effect on the binding affinity,
(4) the in vivo tests of the fluorinated inhibitors, and
(5) the generation of human monoclonal antibodies against MMP-3 and MMP-9.

Funding Scheme

NET - Research network contracts

Coordinator

NATIONAL RESEARCH COUNCIL OF ITALY
Address
Via Mancinelli 7
20131 Milano
Italy

Participants (5)

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
Address
Hopital Henri Mondor, 51 Avenue Du Gal De Lattre D
94010 Creteil
MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.
Germany
Address
18A,am Klopferspitz 18A
82152 Planegg / Krailling
PHILOGEN SRL
Italy
Address
Centro Di Biotechnologie Avanzate, Largo Rosanna B
53100 Siena
SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZUERICH
Switzerland
Address
Winterthurerstrasse 190
8057 Zurich
UNIVERSITE DE PARIS-SUD XI
France
Address
Rue Jean-baptiste Clément 5, Tour D, Etage 5
92296 Chatenay Malabry