771437-08-2Relevant academic research and scientific papers
Inhibition of 14-3-3/Tau by hybrid small-molecule-peptides operating via two different binding modes
Andrei, Sebastian Alexandru,Meijer, Femke,Neves, Joao,Brunsveld, Luc,Landrieu, Isabelle,Ottmann, Christian,Milroy, Lech-Gustav
, (2018/05/15)
Current molecular hypotheses have yet to deliver marketable treatments for Alzheimer's disease (AD), arguably due to a lack of basic knowledge of AD biology, and an overreliance on conventional drug modalities. Protein-protein interactions (PPIs) are emerging drug targets, which show promise for the treatment of e.g. cancer, but are still underexploited for treating neurodegenerative diseases. 14-3-3 binding to phosphorylated Tau is a promising PPI drug target based on its reported destabilizing effect on microtubules, leading to enhanced neurofibrillary tangle formation as a potential cause of AD-related neurodegeneration. Inhibition of 14-3-3/Tau may therefore be neuroprotective. Previously, we reported the development of modified peptide inhibitors of 14-3-3/Tau using a novel structure-guided approach. Here, we report further efforts to optimize the binding mode and activity of our modified Tau peptides through a combination of chemical synthesis, biochemical assays, X-ray crystallography and NMR spectroscopy studies. Most notably, we were able to characterize two different high-affinity binding modes, both of which inhibited 14-3-3-binding to full-length PKA-phosphorylated Tau protein in vitro. Our findings, besides producing useful tool inhibitor compounds for studying 14-3-3/Tau, have enhanced our understanding of the molecular parameters for inhibiting 14-3-3/Tau, which are important milestones toward the establishment of our 14-3-3 PPI hypothesis.
Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors
Ferraris, Dana,Ko, Yao-Sen,Calvin, David,Chiou, Tiffany,Lautar, Susan,Thomas, Bert,Wozniak, Krystyna,Rojas, Camilo,Kalish, Vincent,Belyakov, Sergei
, p. 5579 - 5583 (2007/10/03)
In this paper the synthesis and structure-activity relationships of two classes of electrophile-based DPP IV inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The in vitro potency, stability and ex vivo experiments were performed on select compounds within these series to determine their inhibitory capacity in plasma. In this paper, the synthesis and structure-activity relationships (SAR) of two classes of electrophile-based dipeptidyl peptidase IV (DPP IV) inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The SAR of these series demonstrate that the 2-thiazole, 2-benzothiazole, and 2-pyridylketones are optimal S1′ binding groups for potency against DPP IV. In addition, both cyclohexyl glycine (CHG) and octahydroindole carboxylate (OIC) serve as the most potent S2 binding groups within each series. Stereochemistry at the α-position of the central ring is relevant to potency within the ketopyrrolidines series, but not in the ketoazetidine series. Finally, the ketoazetidines display enhanced stability over the corresponding ketopyrrolidines, while maintaining their potency. In fact, certain stabilized ketoazetidines can maintain their in vitro potency and inhibit DPP IV in the plasma for up to 6 h.
