To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition.
This short review highlights some recent advances in matrix metalloproteinase inhibitor (MMPi) design and development. Three distinct approaches to improved MMP inhibition are discussed: (1) the identification and investigation of novel zinc-binding groups (ZBGs), (2) the study of non-zinc-binding MMPi, and (3) mechanism-based MMPi that form covalent adducts with the protein. Each of these strategies is discussed and their respective advantages and remaining challenges are highlighted. The studies discussed here bode well for the development of ever more selective, potent, and well-tolerated MMPi for treating several important disease pathologies.
Jacobsen
Jennifer A
JA
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, USA.
Major Jourden
Jody L
JL
Miller
Melissa T
MT
Cohen
Seth M
SM
D000818:Animals; D015195:Drug Design; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000145:classification; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity / Q000187:drug effects; D015032:Zinc / Q000378:metabolism*
D011480:Protease Inhibitors; D045726:Metalloproteases; D015032:Zinc