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详细内容
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SAFit2 is a novel, selective FK506-binding protein 51 (FKBP51) antagonist with a Ki of 6 nM and also enhances AKT2-AS160 binding.
SAFit2 is a novel, selective FK506-binding protein 51 (FKBP51) antagonist with a Ki of 6 nM in chemical assay and also enhances AKT2-AS160 binding[1]. SAFit2 treatment increases the expression of pAKT2 (soleus and EDL muscle) and pAS160 (EDL muscle) in WT cells, but there is no effect of FKBP51 antagonism in 51KO cells. Moreover, following SAFit2 treatment, GLUT4 expression increases in the membrane fraction of primary EDL myotubes from WT mice, but not from 51KO mice[2].
It is found that 30 days of SAFit2 administration leads to a reduction in body weight under both control and high-fat diet (HFD) conditions. SAFit2 significantly increases phosphorylated AKT2 and AS160 in EDL muscle and likewise increases expression of GLUT4 at the membrane in soleus muscle[2]. When SAFit2 is applied 1 h before testing, no alterations in anxiety-related behavior are observed. However, SAFit2 treatment induces an anxiolytic phenotype in mice injected 16 h prior testing, which is reflected in a significantly increased open arm time in the elevated plus maze (EPM) (z=-2.183, p<0.05). SAFit2 treatment leads to a significantly reduced latency to enter the lit compartment (z=-2 to 265, p<0.05), as well as a significantly increased distance traveled (t(20)=-2.371, p<0.05) in the lit compartment[3].
[1]. Gaali S, et al. Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51. J Med Chem. 2016 Mar 24;59(6):2410-22. [2]. Balsevich G, et al. Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nat Commun. 2017 Nov 23;8(1):1725. [3]. Hartmann J, et al. Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties. J Neurosci. 2015 Jun 17;35(24):9007-16.
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