Matrix metalloproteinase protein inhibitors: highlighting a new beginning for metalloproteinases in medicine

Abstract

The development of therapeutic matrix metalloproteinase (MMP) inhibitors has evolved from broad-spectrum peptidomimetic inhibitors with deleterious side effects, to highly selective agents. These range from small molecules to antibodies, antisense inhibitors, and engineered N-terminal tissue inhibitors of metalloproteinase domain. The advances in inhibitor design along with promising new global molecular insights into MMP structures, the protease web, and the role of extracellular matrix in diseases have contributed toward a renewed interest in using MMPs as valid drug targets. This review aims to address the advances and challenges concerning the design, development, and current status of anti-MMP agents in this new era of post-broad-spectrum MMP inhibitors. Highly selective inhibitors of MMPs promise to usher in an era of specific targeting of diseased tissue proteolysis networks, with markedly reduced negative repercussions, and to uncover the molecular and mechanistic roles of MMP isoforms in cancer, inflammation, and infection.

Distinct Metalloproteinase Expression and Functions in Systemic Sclerosis and Fibrosis: What We Know and the Potential for Intervention

“…Novel methods for targeting metalloproteinases are necessary, with increased specificity and localized delivery to fibrotic sites. Developing selective synthetic peptides to block catalytic functions, targeting unique MMP domains to alter function, or manipulating endogenous MMP regulators like microRNAs represent some potential avenues of investigation (Li and Li, 2013;Mohan et al, 2016) From what is currently known regarding MMPs in skin and lungs of SSc patients, there are likely two main functions of MMPs, first as mediators of inflammation and tissue damage, and second as contributors to ECM remodeling. As previously mentioned, collagenases like MMP1 and MMP3 are reduced in settings of greater SSc skin fibrosis, and experimental models suggest that increasing their levels or activity may have beneficial effects.…”

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

“…Given the challenges of developing selective MMP inhibitors that target the catalytic site, exosites outside the catalytic site are now also being explored, as referred above. − However, the relatively small size of peptides and/or small molecules limits the possibilities of targeting more specific interactions in more distant exosites. This goal can be more easily reached with emerging protein-based agents. − Indeed, highly selective engineered mAb (or nanobodies) directed against different MMPs, including MMP-2, -8, -9, -13, and MT1-MMP, were developed targeting either exosites or the catalytic site. ,− Another approach is to try to mimic the endogenous regulatory system of MMPs with endogenous-like inhibitors, i.e., TIMPs or pro-domain analogues, which are nontoxic and well-known . In this context, protein engineering tools have been used to design a family of N-terminally modified TIMPs .…”

Local Mutations Can Serve as a Game Changer for Global Protein Solvent Interaction

“…Each protease uniquely influences the properties of its substrate within the ECM and is associated with tissue-specific processes. 3 , 7 MMP upregulation has been connected to several types of cancers as well as inflammatory diseases. 8 − 10 As MMPs have a conserved catalytic site, the development of MMP inhibitors (MMPIs) that exhibit sufficient specificity and selectivity to target one member of the family is of fundamental interest.…”

“…Each protease uniquely influences the properties of its substrate within the ECM and is associated with tissue-specific processes. , MMP upregulation has been connected to several types of cancers as well as inflammatory diseases. − As MMPs have a conserved catalytic site, the development of MMP inhibitors (MMPIs) that exhibit sufficient specificity and selectivity to target one member of the family is of fundamental interest . One solution is the development of protein engineered (PE) inhibitors, such as antibodies or TIMPs (tissue inhibitors of MMPs), that are based on MMP protein structures and target not only the catalytic site but nearby surface exposed residues which vary among family members .…”