2976-75-2Relevant articles and documents
Synthesis and optimization of peptidomimetics as HIV entry inhibitors against the receptor protein CD4 using STD NMR and ligand docking
Neffe, Axel T.,Bilang, Matthias,Meyer, Bernd
, p. 3259 - 3267 (2006)
We recently described the design and synthesis of a novel CD4 binding peptidomimetic as a potential HIV entry inhibitor with a KD value of ～35 M and a high proteolytic stability [A. T. Neffe and B. Meyer, Angew. Chem., Int. Ed., 2004, 43, 2937-2940]. Based on saturation transfer difference (STD) NMR analyses and docking studies of peptidomimetics we now report the rational design, synthesis, and binding properties of 11 compounds with improved binding affinity. Surface plasmon resonance (SPR) resulted in a KD = 10 M for the best peptidomimetic XI, whose binding affinity is confirmed by STD NMR (KD = 9 M). The STD NMR determined binding epitope of the ligand indicates a very similar binding mode as that of the lead structure. The binding studies provide structure activity relationships and demonstrate the utility of this approach. The Royal Society of Chemistry 2006.
SELECTIVE NON-CYCLIC NUCLEOTIDE ACTIVATORS FOR THE CAMP SENSOR EPAC1
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Page/Page column 00165; 00166; 00198; 00229, (2021/09/26)
The invention relates generally to novel EPAC1 activators, such as Formula (I) and (II) and the preparation thereof as well as the use of EPAC1 activators disclosed herein as to selectively activate EPAC1 in cells.
Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators
Wang, Pingyuan,Luchowska-Stańska, Urszula,Van Basten, Boy,Chen, Haiying,Liu, Zhiqing,Wiejak, Jolanta,Whelan, Padraic,Morgan, David,Lochhead, Emma,Barker, Graeme,Rehmann, Holger,Yarwood, Stephen J.,Zhou, Jia
, p. 5159 - 5184 (2020/06/03)
Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.
