131990-88-0Relevant academic research and scientific papers
Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors
Lawandi, Janice,Toumieux, Sylvestre,Seyer, Valentine,Campbell, Philip,Thielges, Sabine,Juillerat-Jeanneret, Lucienne,Moitessier, Nicolas
experimental part, p. 6672 - 6684 (2010/04/28)
Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.
Cyclic hexapeptides and chimeric peptides as mimics of tendamistat
Etzkorn, Felicia A.,Guo, Tao,Lipton, Mark A.,Goldberg, Steven D.,Bartlett, Paul A.
, p. 10412 - 10425 (2007/10/02)
We describe the design and evaluation of structural mimics of tendamistat, a 74-residue proteinaceous inhibitor of α-amylase. Cyclic hexapeptides were designed in which the sequence Trp-Arg-Tyr is constrained to the i + 1 to i + 3 positions of a type I β-
