Recent insights into natural product inhibitors of matrix metalloproteinases

Abstract

Members of the matrix metalloproteinase (MMP) family have biological functions that are central to human health and disease, and MMP inhibitors have been investigated for the treatment of cardiovascular disease, cancer and neurodegenerative disorders. The outcomes of initial clinical trials with the first generation of MMP inhibitors proved disappointing. However, our growing understanding of the complexities of the MMP function in disease, and an increased understanding of MMP protein architecture and control of activity now provide new opportunities and avenues to develop MMP-focused therapies. Natural products that affect MMP activities have been of strong interest as templates for drug discovery, and for their use as chemical tools to help delineate the roles of MMPs that still remain to be defined. Herein, we highlight the most recent discoveries of structurally diverse natural product inhibitors to these proteases.

Fig. 1. Roles of MMPs in human health and disease.

Fig. 2. Structural features of the catalytic domain of MMP-2. a) The crystal structure of MMP-2 catalytic domain, PDB code 1QIB.pdb, revealed that three histidines bind to an active site Zn²⁺ ion colored in dark grey. A conserved-glutamate residue is also present that is required for the catalytic mechanism of water-mediated nucleophilic attack on the substrate peptide bond. A conserved methionine residue forms the hydrophobic base of the active site. Protein surface is depicted in light grey. b) The size of the S12 site pocket of MMPs can help provide substrate specificity. MMP-2 has a deep, extended S12 pocket, as highlighted by the docking of anacardic acid, cyan backbone, into the protein structure that results in the extended aliphatic chain of this natural product binding into the S12 pocket. Major cavities of the MMP-2 catalytic domain structure, including S12, are highlighted in light grey.

Fig. 3. Regulation of MMP activities. Intracellular MMP activation may occur by the action of convertases, including Furin, or at the cell surface. For example, MT1-MMP dimers can form trimeric complexes with TIMP and MMP-2, which results in cleavage of the MMP-2 propeptide, and thereby releasing activated MMP-2 into the extracellular milieu. MMPs can also be activated without removal of the inhibitory propeptide domain, by reactive oxygen species (ROS), reactive nitrogen species (ONOO^–) or by glutathiolation. The activity of MMPs can also modulated by activators, such as extracellular matrix metalloproteinase inducer (EMMPRIN) and inhibited by tissue inhibitor of metalloproteinases (TIMPs) and/or reversion-inducing-cysteine-rich protein with Kazal motifs (RECK). Growth factors, such as PDGF and TGF-β, can enhance the production of TIMPs. Cytokines or CD40 signaling can promote the exocytosis of Pro-MMPs stored in granules.

Fig. 4. Natural products that inhibit or suppress expression of MMPs have remarkably diverse structures and derive from a variety of marine and terrestrial sources.

Scheme 1. Synthesis of natural and unnatural anacardic acid analogs for isoform-specific bioactivity profiling.