A new role for old ligands: discerning chelators for zinc metalloproteinases.
In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs) several new zinc-binding groups (ZBGs) based on pyridine-derived or aza-macrocycle chelators have been examined. Fluorescence-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-1, MMP-3, and anthrax lethal factor (LF). Many of these ligands were found to be remarkably potent, with IC50 values as much as 185-fold lower than that found for acetohydroxamic acid. These ligands are proposed to be more selective "warheads" for the inhibition of metalloenzymes that contain Zn2+ versus other metal ions at their active site.
Jacobsen
Faith E
FE
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Lewis
Jana A
JA
Cohen
Seth M
SM
D001665:Binding Sites; D002413:Cations, Divalent; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
D002413:Cations, Divalent; D002614:Chelating Agents; D006877:Hydroxamic Acids; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C006358:acetohydroxamic acid; D020782:Matrix Metalloproteinases; D015032:Zinc