Design of Inhibitors for Proteolytic Cascades 17 Matrix metalloprotease inhibitors: design from structure

The zincand calcium-dependent family of proteins called the MMPs (matrix metalloproteases) are collectively responsible for the degradation of the extracellular matrix. The enzymes are synthesized as zymogens, and under physiological conditions are selectively regulated by endogenous inhibitors. An imbalance between the active enzymes and their natural inhibitors leads to the accelerated destruction of connective tissue associated with the pathology of diseases such as arthritis, cancer, multiple sclerosis and cardiovascular diseases. The potential for using specific enzyme inhibitors as therapeutic agents to redress this balance has led to intensive research focused on the design, synthesis and molecular deciphering of low-molecular-mass inhibitors of this family of proteins. The design of early MMP inhibitors was based on the scissile site sequence of peptide substrates, with moieties customized to chelate the critical zinc ion at the enzymes’ active site. These initial efforts were supported by X-ray and NMR data on MMP complexes, exploiting sequence and structural differences in the principal specificity pocket of the enzymes, leading to subtype-selective MMP inhibitors. This review will provide a critical appraisal of the design principles that have been utilized in generating molecules that inhibit MMPs, and explore issues relevant to obtaining clinical efficacy of MMP inhibitor-based therapies. Introduction The extracellular matrix cascade [1], which includes the MMPs (matrix metalloproteases), is involved in events such as embryogenesis, wound healing and metastasis, to name but a few [2,3]. MMPs are a zincand calcium-dependent family of proteins that are collectively responsible for the degradation of the extracellular matrix [4]. The enzymes are synthesized as zymogens [5], and under physiological conditions are selectively regulated by endogenous inhibitors. An imbalance between the active enzymes and their natural inhibitors leads to the accelerated destruction of connective tissue, which is associated with the pathology of diseases such as arthritis, cancer, multiple sclerosis and cardiovascular diseases [6–10]. The potential for using specific enzyme inhibitors as therapeutic agents to redress this balance has led to intensive research [11–13] focused on the design, synthesis and molecular deciphering of low-molecular-mass inhibitors of this family of proteins. Design of early MMP inhibitors Cartilage is a complex connective tissue composed of collagen and proteoglycan [14–17]. Collagen, which gives connective tissue its strength and rigidity, is normally resistant to proteases due to its unique supercoiled triple helix structure. However, collagenase (MMP-1) is the only protease capable