@article{3021349,
    title = "Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes",
    author = "Covaleda, G. and Gallego, P. and Vendrell, J. and Georgiadis, D. and Lorenzo, J. and Dive, V. and Aviles, F.X. and Reverter, D. and Devel, L.",
    journal = "Journal of Medicinal Chemistry",
    year = "2019",
    volume = "62",
    number = "4",
    pages = "1917-1931",
    publisher = "American Chemical Society",
    issn = "0022-2623, 1520-4804",
    doi = "10.1021/acs.jmedchem.8b01465",
    keywords = "2 [3 [4 [2 [(2 carboxy 4 phenylbutyl)(hydroxy)phosphoryl] 5 (4 hydroxybenzyl) 4,7,16,29 tetraoxo 9,12,19,22,25 pentaoxa 3,6,15,28 tetraazahentriacontan 31 yl]phenyl] 5 [1,1 dimethyl 6,8 disulfo 3 (4 sulfobutyl) 1,3 dihydro 2h benzo[e]indol 3 ium;  2 [[[1 (n acetyl glutamyl 1 amido)ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 (n acetyl leucylamido) 2 phenylethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 (n acetyl leucylamido)ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 (n acetyl prolylamido)ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 (n acetyl serylamido)ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 (n acetyl tyrosylamido)ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 (n alpha acetyl lysylamido)ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 [n [2 [2 (2 acetamidoethoxy)ethoxy]acetyl]tyrosylamido]ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  2 [[[1 [n [2 [2 (2 aminoethoxy)ethoxy]acetyl]tyrosylamido]ethyl](hydroxy)phosphoryl]methyl] 4 phenylbutanoic acid;  carboxypeptidase A;  carboxypeptidase A1;  carboxypeptidase A2;  carboxypeptidase A3;  carboxypeptidase A4;  carboxypeptidase B;  carboxypeptidase B1;  carboxypeptidase D;  metalloproteinase inhibitor;  phosphinic acid derivative;  pseudopeptide;  thrombin activatable fibrinolysis inhibitor;  unclassified drug;  carboxypeptidase A;  enzyme inhibitor;  fluorescent dye;  indole derivative;  oligopeptide;  phosphinic acid derivative;  protein binding, amino terminal sequence;  Article;  binding affinity;  cell viability;  chemical modification;  controlled study;  crystal structure;  cytotoxicity;  drug design;  drug protein binding;  drug synthesis;  drug targeting;  enzyme inhibition;  enzyme specificity;  female;  human;  human cell;  Michael addition;  structure activity relation;  chemistry;  confocal microscopy;  enzyme active site;  fluorescence microscopy;  HEK293 cell line;  HeLa cell line;  kinetics;  metabolism;  procedures;  synthesis, Carboxypeptidases A;  Catalytic Domain;  Enzyme Inhibitors;  Fluorescent Dyes;  HEK293 Cells;  HeLa Cells;  Humans;  Indoles;  Kinetics;  Microscopy, Confocal;  Microscopy, Fluorescence;  Oligopeptides;  Phosphinic Acids;  Protein Binding",
    abstract = "Metallocarboxypeptidases (MCPs) of the M14 family are Zn 2+ -dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic pseudopeptides presented here constitute the first example of chemical probes useful to selectively report on type-A MCPs activity in complex media. © 2019 American Chemical Society."
}