Potent inhibition of MMP-9 by a novel sustained-release platform attenuates left ventricular remodeling following myocardial infarction.

Sustained drug-release systems prolong the retention of therapeutic drugs within target tissues to alleviate the need for repeated drug administration. Two major caveats of the current systems are that the release rate and the timing cannot be predicted or fine-tuned because they rely on uncontrolled environmental conditions and that the system must be redesigned for each drug and treatment regime because the drug is bound via interactions that are specific to its structure and composition. We present a controlled and universal sustained drug-release system, which comprises minute spherical particles in which a therapeutic protein is affinity-bound to alginate sulfate (AlgS) through one or more short heparin-binding peptide (HBP) sequence repeats.

Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy.

Crosstalk of the oncogenic matrix metalloproteinase-9 (MMP9) and one of its ligands, CD44, involves cleavage of CD44 by the MMP9 catalytic domain, with the CD44-MMP9 interaction on the cell surface taking place through the MMP9 hemopexin domain (PEX). This interaction promotes cancer cell migration and invasiveness. In concert, MMP9-processed CD44 induces the expression of MMP9, which degrades ECM components and facilitates growth factor release and activation, cancer cell invasiveness, and metastasis.

Targeting the MMP-14/MMP-2/integrin αβ axis with multispecific N-TIMP2-based antagonists for cancer therapy.

The pathophysiological functions of the signaling molecules matrix metalloproteinase-14 (MMP-14) and integrin αβ in various types of cancer are believed to derive from their collaborative activity in promoting invasion, metastasis, and angiogenesis, as shown and The two effectors act in concert in a cell-specific manner through the localization of pro-MMP-2 to the cell surface, where it is processed to intermediate and matured MMP-2. The matured MMP-2 product is localized to the cell surface via its binding to integrin αβ The MMP-14/MMP-2/integrin αβ axis thus constitutes an attractive putative target for therapeutic interventions, but the development of inhibitors that target this axis remains an unfulfilled task. To address the lack of such multitarget inhibitors, we have established a combinatorial approach that is based on flow cytometry screening of a yeast-displayed N-TIMP2 (-terminal domain variant of issue nhibitor of etalloroteinase-2) mutant library.

Development of High Affinity and High Specificity Inhibitors of Matrix Metalloproteinase 14 through Computational Design and Directed Evolution.

Degradation of the extracellular matrices in the human body is controlled by matrix metalloproteinases (MMPs), a family of more than 20 homologous enzymes. Imbalance in MMP activity can result in many diseases, such as arthritis, cardiovascular diseases, neurological disorders, fibrosis, and cancers. Thus, MMPs present attractive targets for drug design and have been a focus for inhibitor design for as long as 3 decades.