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.

Doing double duty: A metalloproteinase inhibitor that can be activated by reactive oxygen species (ROS) has been designed to protect the blood‐brain barrier (BBB) in ischemic reperfusion injury. By both neutralizing damaging ROS and inhibiting degradative metalloproteinases, a single compound can eliminate both threats to the BBB upon activation.

A series of self-immolative boronic ester protected methyl salicylates and metal-binding groups with various linking strategies have been investigated for their use in the design of matrix metalloproteinase proinhibitors.

No abstract

This study details the development of matrix metalloproteinase inhibitor prodrugs (proMMPi) that are activated in the presence of reactive-oxygen species (ROS). Conventional matrix metalloproteinase inhibitors (MMPi) utilize a zinc-binding group (ZBG) that chelates to the catalytic zinc(II) ion of matrix metalloproteinases (MMPs) to inhibit their activity. To create ROS-sensitive prodrugs, sulfonate esters were used as a protecting group for the ZBG to block their metal binding ability. Surprisingly, these sulfonate esters were found to be cleaved by H2O2 only when the ZBG contained an N-oxide donor atom moiety. Sulfonate ester derivatives of full-length MMPi based on these ROS-triggerable systems were synthesized. It was found that proMMPi with sulfonate ester protecting groups showed relatively high rates of cleavage in the presence of H2O2 to release the active MMPi. In vitro MMP inhibition studies confirmed a significant increase in inhibitory activity of proMMPi upon addition of H2O2, demonstrating the use of sulfonate esters to act as cleavable triggers for ROS-activated prodrugs.

Matrix metalloproteinase inhibitors (MMPi) possessing a glucose protecting group on the zincbinding group (ZBG) show a dramatic increase in inhibitory activity upon cleavage by β-glucosidase.Matrix metalloproteinases (MMPs) are a ubiquitous class of zinc(II)-dependent hydrolytic enzymes that have been associated with a wide range of pathologies including cancer, arthritis, heart disease, and stroke. [1][2][3] Clinical trials of matrix metalloproteinase inhibitors (MMPi) have frequently been hampered by the onset of musculoskeletal syndrome (MSS), which manifests as severe joint pain, and has been attributed to non-specific, systemic inhibition of MMPs and other metalloenzymes. 4,5 One approach to eliminate or minimize MSS and other complications would be to develop prodrugs or 'proinhibitors' that are triggered in a localized fashion, hence restricting inhibitory activity both spatially and temporally. The prodrug concept has been applied to a variety of targets, triggered by stimuli such as light, changes in pH, and enzymatic activity. 6,7 A common strategy in the development of prodrugs and proinhibitors is through the use of carbohydrate protecting groups. The development of glycoconjugate prodrugs offers the ability to increase water solubility, enhance targeting, and minimize the side effects associated with systemic delivery of cytotoxic drugs. [8][9][10][11] The use of glycoside protecting groups, such as glucoside moieties, have been reported for use with targeted treatments such as ADEPT (antibody directed enzyme prodrug therapy) and PMT (prodrug monotherapy). 12-14 The ADEPT approach, developed over 20 years ago, has been widely investigated as a means to deliver drugs specifically to cancerous tissue and has shown promise in both animal studies and clinical trials. [15][16][17] Glucose-derivatized compounds can also enhance uptake in cancer cells [18][19][20] and the brain. 9,10,21 Metalloenzyme inhibitors such as MMPi are particularly suitable to the proinhibitor approach because such compounds generally employ a metal-binding moiety, which if blocked with a protecting group, abolishes inhibitory activity. Specifically, using glucose as a protecting group, a proinhibitor MMPi can be developed to release the active MMPi in the presence of β-glucosidase to restore MMP inhibitory activity. Surprisingly, metalloenzyme proinhibitors have not been widely investigated and very few proinhibitors have been designed for MMPs. [22][23][24][25][26][27][28][29] Only one example of a glycoside MMP proinhibitor has been prepared; however, efforts to release the active MMPi through enzymatic cleavage proved unsuccessful. 27 In this report, we show that an MMPi can be formulated and inactivated as a proinhibitor, deprotected and released by an enzymatic signal, and hence exhibit triggered control over inhibitory activity. The compounds described here allow for spatial and temporal control of MMP inhibition, † Electronic supplementary information (ESI) available: Synthetic details, characterization of all comp...