Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics

Abstract

The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.

Keywords: ADAMs; MMP inhibitors; MMP-responsive therapeutics; MMPs; TIMPs; a disintegrin and metalloproteases; matrix metalloproteinases; metalloproteinases; metzincins; tissue inhibitors of metalloproteinases.

Figure 1

Schematic representation of matrix metalloproteinases (MMPs), a-disintegrin and metalloproteinases (ADAMs), and a-disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs). The structural domains of different metalloproteinases (MPs) are displayed. GPI, Glycosylphosphatidylinositol-anchoring sequence; EGF, epidermal growth factor-like domain.

Figure 2

Metalloproteainses (MPs) in developing diseases.

Figure 3

Engineering and design of tissue inhibitors of metalloproteinases (TIMP) scaffolds for targeting specific MMPs with high affinity and selectivity. Combination of rational design (left) and directed evolution using yeast cell surface display and high throughput screening (right) were used to engineer TIMP-1 variants targeting MMP-3 [32]. TIMP-1mutant; shown in blue (N-terminal domain) and green (C-terminal domain), in complex with MMP-3 catalytic domain (MMP-3cd); shown in dark orange protein crystal structure (PDB ID: 6N9D) was shown with the potential regions for random mutation highlighted with magenta spheres.

Figure 4

MMP-responsive therapeutics—(A) Activation of pro-drug by MMP degradation; MMP cleavable tag (yellow/orange arrow) is attached to the inactivated drug. The drug gets activated by cleavage of the MMP substrate, (B) MMP-resonsive nanoparticles, containing hydrophilic–hydrophobic elements, go through transition rearrangement after exposure to the MMP degradation.