论文部分内容阅读
Collagen serves as a structural scaffold and a barrier between tissues, and thus collagen catabolism (collagenolysis) is required to be a tightly regulated process in normal physiology.In turn, the destruction or damage of collagen during pathological states plays a role in tumor growth and invasion, cartilage degradation, or atherosclerotic plaque formation and rupture.Several members of the matrix metalloproteinase (MMP) family possess collagenolytic activity.Our laboratory has developed triple-helical peptide (THP) substrates and inhibitors for MMPs, with the goal of using these model systems to disseet collagenolytic behavior and design potentially selective inhibitors.We have taken advantage of secondary binding sites (exosites) to achieve selectivity within the MMP family.Constructs incorporating phosphinate transition state analogs and exosite binding regions have allowed us to create MMP inhibitors with high affinities and selectivities not observed previously.J.Am.Chem.Soc.129, 10408 (2007); J.Biol.Chem.283, 20087 (2008).In turn, assays with THP substrates have yielded novel MMP exosite binders J.Biol.Chem.283, 20087 (2008); Bioorg.Med.Chem., in press (2008).Ultimately, we are utilizing information about collagenolytic mechanisms to design inhibitors that target proteases implicated in cancer progression (MMP-2, MMP-9, and MT1-MMP) while sparing proteases with host-beneficial functions (MMP-3 and MMP-8).