A group of peptide-based, long-acting,
stable, highly selective
cholecystokinin 1 receptor (CCK-1R) agonists with the potential to
treat obesity has been identified and characterized, based on systematic
investigation of synthetic CCK-8 analogues with N-terminal linkage
to fatty acids. Sulfated Tyr in such compounds was stable in neutral
buffer. CCK-1R selectivity was achieved mostly by introducing d-N-methyl-Asp instead of Asp at the penultimate
position of CCK-8. Our compound 9 (NN9056) showed similar
in vitro CCK-1R potency and CCK-1R affinity as CCK-8, very high selectivity
for CCK-1R over the cholecystokinin 2 receptor (CCK-2R), strong
reduction of food intake in lean pigs for up to 48 h after one subcutaneous
injection without adverse effects, a plasma half-life of 113 h in
minipigs after intravenous injection, and acceptable chemical stability
in a neutral liquid formulation. In addition, we found a highly selective
CCK-2R agonist by replacing Gly in a CCK-8 derivative with Glu.
The online coupling of microchip electrophoresis (ME) as a fast, highly efficient, and low-cost miniaturized separation technique to mass spectrometry (MS) as an information-rich and sensitive characterization technique results in ME-MS an attractive tool for various applications. In this paper, we review the basic concepts and latest advances in technology for ME coupled to MS during the period of 2016-2021, covering microchip materials, structures, fabrication techniques, and interfacing to electrospray ionization (ESI)-MS and matrix-assisted laser desorption/ionization-MS. Two critical issues in coupling ME and ESI-MS include the electrical connection used to define the electrophoretic field strength along the separation channel and the generation of the electrospray for MS detection, as well as, a miniaturized ESI-tip. The recent commercialization of ME-MS in zone electrophoresis and isoelectric focusing modes has led to the widespread application of these techniques in academia and industry. Here we summarize recent applications of ME-MS for the separation and detection of antibodies, proteins, peptides, carbohydrates, metabolites, and so on. Throughout the paper these applications are discussed in the context of benefits and limitations of ME-MS in comparison to alternative techniques.
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