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October 2000
Vol. 3, No. 8, p. 11.

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Metalloproteinase inhibitor design

Cancer turns deadly when cells break from the pack and take up residence elsewhere in the body. Facilitating this migration is a family of enzymes called matrix metalloproteinases (MMPs), which are known to help cells spread and set up a new blood supply to support tumor growth. Now, chemists have figured out a way to scramble this process by designing a selective inhibitor that jams the enzyme like a key in a lock, bringing its cancer-spreading activity to an abrupt halt (J. Am. Chem. Soc. 2000, 122, 6799–6800).

Although MMPs are crucial to processes such as organ development, wound healing, angiogenesis, and implantation of the fetus, excessive MMP activity has been implicated in disorders such as metastasis, arthritis, and cardiovascular and autoimmune diseases. Two MMPs in particular—gelatinases known as MMP-2 and MMP-9—have been fingered in the process of promoting tumor metastasis and angiogenesis.

But given the number and structural similarity of MMPs, indiscriminate inhibition could mean dire consequences for the organism, says chemist Shahriar Mobashery, director of the Institute for Drug Design at Wayne State University (Detroit). To date, MMP inhibitors have been designed to chelate the critical zinc ion at the enzymes’ active site, which has resulted in broad-spectrum inhibitors.
reaction pathways
Covalent inhibitor binding. In a reaction mediated by the zinc ion, the inhibitor becomes covalently bound to an active site glutamate residue.

Instead, he and his group designed an inhibitor that was highly selective for gelatinase, based on how the enzyme functions. Once bound to the active site, the inhibitor initiates a reaction that is mediated by the zinc ion at the active site. In the process, the inhibitor becomes covalently attached to the enzyme, irreversibly inhibiting catalysis.

Plans are in the works to determine the effectiveness of the inhibitor at preventing breast tumor metastasis and controlling inflammation associated with infection in animal models.


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