To bind zinc or not to bind zinc: An examination of innovative approaches to improved metalloproteinase inhibition

Abstract

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.

Caesalpinia sappan extract inhibits IL1β-mediated overexpression of matrix metalloproteinases in human chondrocytes

“…Since exacerbated production and activation of MMPs is associated with rheumatoid arthritis and OA, MMPs represent promising pharmacological targets for the treatment of arthritic diseases (Jacobsen et al 2010). Strategies for MMP inhibition include direct MMP inhibition (by TIMPs, small molecule MMP inhibitors, or antibodies) and indirect MMP inhibition targeting signaling pathways that lead to MMP expression.…”

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C 82 (OH) 22 and its implication for de novo design of nanomedicine

“…4), thereby discarding the direct inhibitory mechanism. Interestingly, recent studies of the MMP inhibitors are focusing more on the indirect inhibition mechanism (19). Because the zinc-binding sites are highly homologous over various MMPs (20,21), a small-molecular antagonist directly targeting the catalytic site often fails to selectively inhibit a target MMP, causing various side effects (22).…”

“…Our findings also imply that the pharmacokinetic action of nanoparticles could be markedly different from the traditional target-based molecular drugs. The non-zinc active site binding naturally avoids the difficulty of using complicated quantum mechanics-based energy functions in computational MMP inhibitor development, which has drawn tremendous effort (19).…”

Sulfonate-Containing Thiiranes as Selective Gelatinase Inhibitors

“…The most explored of such a zinc chelator in inhibitors has been the hydroxamate group. 7 Unfortunately, hydroxamates suffer from many shortcomings, which we will not discuss here in the interest of brevity. Newer generations of inhibitors utilize carboxylates, phosphates and phosphinates, pyrimidines, and thiolates as the entities that interact with the active-site zinc ion.…”

“…Newer generations of inhibitors utilize carboxylates, phosphates and phosphinates, pyrimidines, and thiolates as the entities that interact with the active-site zinc ion. 5,7,10 A few years prior, we disclosed the family of thiirane-based selective gelatinase (MMP-2 and MMP-9) inhibitors, of which compound 1 is the prototypic member ( Figure 1). 11 Compound 1 was shown previously to be a potent inhibitor of gelatinases with time-dependent kinetics for the inhibition, a hallmark of either covalent inhibition or slow-binding inhibition.…”