The Weizmann Institute of Science, Department of Biological Regulation , Rehovot 76100 , Israel
Expert Opin Drug Discov. 2011 May;6(5):527-42. doi: 10.1517/17460441.2011.560936. Epub 2011 Apr 21.
MMPs (matrix metalloproteinases) and ADAMs (a disintegrin and metalloproteinases) are endopeptidases central to the degradation and remodeling of the extracellular matrix. These proteases also exhibit regulatory activity in cell signaling pathways and thus tissue homeostasis under normal conditions and in many diseases. Consequently, individual members of the MMP and ADAM protein families were identified as important therapeutic targets. However, designing effective inhibitors in vivo for this class of enzymes appears to be extremely challenging. This is attributed to the broad structural similarity of their active sites and to the dynamic functional interconnectivity of MMPs with other proteases, their inhibitors, and substrates (the so-called degradome) in healthy and disease tissues.
The article covers the progress in designing metalloproteinase inhibitors, based on recent advancements in our understanding of enzyme structures and their function as master regulators. It also discusses the potential of utilizing structure-based drug design strategies in conjunction with systems biology experimental approaches for designing potent and therapeutically effective metalloproteinase inhibitors.
We highlight the use of protein-based drug design strategies, for example, antibodies and protein scaffolds, targeting extracatalytic domains, which are central to proteolytic and non-proteolytic enzyme functions. Such rationally designed function-blocking inhibitors may create new opportunities in disease management and in emerging therapies that require control of dysregulated MMP activity without causing severe side effects. Importantly, the lessons learned from studying these protein-based inhibitors can be implemented to design new and effective small or medium sized synthetic antagonists.
基质金属蛋白酶（MMPs）和解整合素金属蛋白酶（ADAMs）是细胞外基质降解和重塑的核心内肽酶。这些蛋白酶在细胞信号通路中也表现出调节活性，因此在正常情况下和许多疾病中都维持着组织内环境稳定。因此，MMP 和 ADAM 蛋白家族的各个成员被确定为重要的治疗靶点。然而，设计针对这类酶的有效抑制剂在体内似乎极具挑战性。这归因于其活性位点的广泛结构相似性，以及 MMP 与其他蛋白酶、其抑制剂和底物（所谓的降解组）在健康和疾病组织中的动态功能相互连接性。
本文基于对酶结构及其作为主调控因子的功能的最新理解，综述了设计金属蛋白酶抑制剂的进展。还讨论了结合系统生物学实验方法，利用基于结构的药物设计策略设计有效且具有治疗作用的金属蛋白酶抑制剂的潜力。
我们强调了使用基于蛋白质的药物设计策略，例如针对催化域外区的抗体和蛋白质支架，这些策略是蛋白水解和非蛋白水解酶功能的核心。这种合理设计的功能阻断抑制剂可能为疾病管理和新兴治疗方法创造新的机会，这些方法需要控制失调的 MMP 活性，而不会引起严重的副作用。重要的是，从研究这些基于蛋白质的抑制剂中吸取的经验教训可以用于设计新的、有效的小分子或中分子合成拮抗剂。
