Cell-permeable ligands

E. R. Hickey, S. Jakes, A. Kabcenell et al. Nonpeptidic, monocharged, cell permeable ligands for the p561ck SH2 domain, J. Med. Chem. 2001, 44, 2421-2431... 

One of the most efficient ways to identify cell-permeable ligands is through the utilization of high-throughput screens. Identification of inhibitors through this method has been hampered by the lack of effective assays. 

D.M. Watterson, S. Mirzoeva, L. Guo, A. Whyte, J.J. Bourguignon, M. Hibert, J. Haiech and L.J. Van Eldik, Ligand modulation of glial activation cell permeable, small molecule inhibitors of serine-threonine protein kinases can block induction of interleukin 1 beta and nitric oxide synthase II, Neurochem. Int. 39 (2001) 459-468. 

Early work on the use of phenylalanine phosphonates in synthetic peptides as SH2 domain ligands and phosphotyrosine phosphatase inhibitors proved the efficicacy of these agents in medicinal chemistry [20, 22], Incorporation of phosphonomethylene alanine (Pma) and phosphonomethylene phenylalanine (Pmp) using nonsense-mediated suppression has also been shown to be feasible using in vitro translation [5], but this has not been used for practical applications, perhaps because of scale-up challenges. Pma and Pmp have not yet been used in vivo in nonsense suppression, presumably because of the limited cell permeability of the amino acids. 

In order to generate a cell permeable PROTAC, an alternative E3 ligase ligand was required. The IkBcx phosphopeptide functioned successfully to recruit the E3 ligase components, but the negatively charged... 

A Zn2+ -responsive dual fluorescence and MRI probe (14) (Scheme 9) based on a porphyrin ligand platform was also designed. Compound 14 is a fluorescent sensor turned on by the presence of Zn +, while the Mn + complex functions as an MRI contrast agent. In the aqueous solution of Zn +, the relaxivity of Mn-14 is significantly altered. Both the metal-free and Mn + complex are efficiently taken up by live cells (HEK-293), and the intracellular zinc can be imaged by either fluorescence or MR. It is the first cell-permeable MRI sensor for the detection of intracellular zinc in both T - and r2-weighted images. 

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