Search for new generation selective inhibitors of MMPs not interacting with the catalytic zinc ion.

 

TITLE

Search for new generation selective inhibitors of MMPs not interacting with the catalytic zinc ion.

STAFF

G. Pochetti
R. Montanari

KEYWORDS

metalloproteinases, zinc-endopeptidases, inflammation, MMP-8, non-Zinc chelating inhibitors, selectivity, X-ray structures

COLLABORATIONS
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università di L'Aquila.

DESCRIPTION

Matrix metalloproteinases (MMPs) belong to a family of zinc-endopeptidases involved in many physiological processes such as ovulation, embryogenesis, angiogenesis, cellular differentiation and wound healing. The MMPs comprise a large family of around
d 30 members sharing common structural and functional elements. The catalytic activity of MMPs is tightly controlled by endogenous inhibitors, such as the tissue inhibitors TIMPs. It is widely appreciated that TIMPs inhibit cell invasion in vitro, tumorigenesis, metastasis in vivo, and angiogenesis. Overexpression of MMP activity, or inadequate control by TIMPs, have been observed and associated with a variety of pathological conditions such as psoriasis, multiple sclerosis, osteoarthritis, rheumatoid arthritis, osteoporosis, Alzheimer's disease, tumor growth and metastasis, and unwanted degradation of extracellular proteins. The development of low molecular weight synthetic inhibitors of MMPs is one approach to the therapeutic treatment of these pathologies. So far no MMP inhibitor has emerged on the market, with the sole exception of doxycycline (Periostat), an antibiotic which nonselectively inhibits MMPs. In fact, first generation inhibitors, generally including a function capable to efficiently chelate the catalytic zinc ion (zinc binding group or ZBG), were affected by lack of selectivity, not only toward the other members of the same family but even to other physiologically important metalloenzymes. For this reason new generation inhibitors not interacting with the catalytic zinc ion have been designed. These inhibitors act exploiting a region involved in substrate binding, the hydrophobic S1' pocket, also named specificity pocket because accounts for the variety in depth and nature of the pocket of all MMPs. Nowadays, among the new generation inhibitors, only selective inhibitors of MMP-13, MMP-12 are known.

In a recent paper (1) our research group reported the X-ray structure of the first two non zinc-chelating inhibitors of human neutrophil collagenase (MMP-8) in the complex with the catalytic domain of the enzyme. Both ligands inhibit MMP-8 with activity in the low nM range and are highly selective versus several other MMPs.

(1) POCHETTI G., MONTANARI R., GEGE C., CHEVRIER C., TAVERAS A.G., MAZZA F. "Extra binding region induced by non-zinc chelating inhibitors into the S1' subsite of matrix metalloproteinase8 (MMP-8)" J.Med.Chem., 2009, 52, 1040-1049,.

Search for new generation selective inhibitors of MMPs not interacting with the catalytic zinc ion. - Img

Figure: Crystal structure of the first two selective, non zinc-chelating inhibitors of MMP-8 in the catalytic domain.

CONTACTS

 

Roberta Montanari
Email : roberta.montanariATic.cnr.it

Tel : +39/06 90672618

 

Last Updated (Tuesday, 21 December 2010 16:58)