Fingleton Barbara
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232-6840, USA.
Semin Cell Dev Biol. 2008 Feb;19(1):61-8. doi: 10.1016/j.semcdb.2007.06.006. Epub 2007 Jul 6.
Matrix metalloproteinases (MMPs) appear to be ideal drug targets--they are disease-associated, extracellular enzymes with a dependence on zinc for activity. This apparently straightforward target, however, is much more complex than initially realized. Although disease associated, the roles for particular enzymes may be healing rather than harmful making broad-spectrum inhibition unwise; targeting the catalytic zinc with specificity is difficult, since other related proteases as well as non-related proteins can be affected by some chelating groups. While the failure of early-generation MMP inhibitors dampened enthusiasm for this type of drug, there has recently been a wealth of studies examining the basic biology of MMPs which will greatly inform new drug trials in this field.
基质金属蛋白酶(MMPs)似乎是理想的药物靶点——它们是与疾病相关的细胞外酶,其活性依赖于锌。然而,这个看似简单的靶点比最初意识到的要复杂得多。尽管与疾病相关,但特定酶的作用可能是促进愈合而非有害,因此进行广谱抑制并不明智;由于其他相关蛋白酶以及非相关蛋白质可能会受到某些螯合基团的影响,特异性靶向催化锌很困难。虽然早期一代MMP抑制剂的失败削弱了人们对这类药物的热情,但最近有大量研究探讨了MMPs的基础生物学,这将为该领域的新药试验提供很多信息。