biostudies-literature00540Mendes DENCI NIH HHSNIGMS NIH HHS167-71https://www.ebi.ac.uk/biostudies/studies/S-EPMC4701619biostudies-literatureUnknown31(1)Membrane-type I matrix metalloproteinases (MT1-MMP) is an enzyme critical to the remodeling and homeostasis of extracellular matrix, and when over expressed it contributes to metastasis and cancer cell progression. Because of its role and implication as a biomarker that is upregulated in various cancers, MT1-MMP has become an attractive target for drug discovery. A small pilot library of peptidomimetics containing a phosphoramidate core as a zinc-binding group was synthesized and tested for inhibitory potency against MT1-MMP. From this library, a novel two residue peptidomimetic scaffold was identified that confers potency against MT1-MMP at submicromolar concentrations. The results of this study confirm that for this scaffold, valine is favored as a P1 residue and leucine in the P1' position. Furthermore, steric tolerance was observed for the N-terminus, thus implicating that a second-generation library could be constructed to extend the scaffold to P2 without concomitant loss of affinity within the MT1-MMP catalytic domain.Journal of enzyme inhibition and medicinal chemistryPhosphoramidate-based peptidomimetic inhibitors of membrane type-1 matrix metalloproteinase.PMC4701619T32GM008336R01 CA140617R01CA140617T32 GM008336Mendes DEWong-On-Wing ABerkman CE54falsePhosphoramidate-based peptidomimetic inhibitors of membrane type-1 matrix metalloproteinase.Membrane-type I matrix metalloproteinases (MT1-MMP) is an enzyme critical to the remodeling and homeostasis of extracellular matrix, and when over expressed it contributes to metastasis and cancer cell progression. Because of its role and implication as a biomarker that is upregulated in various cancers, MT1-MMP has become an attractive target for drug discovery. A small pilot library of peptidomimetics containing a phosphoramidate core as a zinc-binding group was synthesized and tested for inhibitory potency against MT1-MMP. From this library, a novel two residue peptidomimetic scaffold was identified that confers potency against MT1-MMP at submicromolar concentrations. The results of this study confirm that for this scaffold, valine is favored as a P1 residue and leucine in the P1' position. Furthermore, steric tolerance was observed for the N-terminus, thus implicating that a second-generation library could be constructed to extend the scaffold to P2 without concomitant loss of affinity within the MT1-MMP catalytic domain.2016-01-01T00:00:00Z20162020-10-29T12:56:31Z2019-03-27T02:06:16ZS-EPMC47016192581567110.3109/14756366.2015.1010528