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Identification of Small-Molecule Modulators of Diguanylate Cyclase by FRET-Based High-Throughput Screening
摘要： The bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) is a key regulator of cellular motility, the cell cycle, and biofilm formation with its resultant antibiotic tolerance, which can make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c-di-GMP, might be attractive drug targets for control of biofilm formation that is part of chronic infections. We present a FRET-based biochemical high-throughput screening approach coupled with detailed structure–activity studies to identify synthetic small-molecule modulators of the diguanylate cyclase DgcA from Caulobacter crescentus. We identified a set of seven small molecules that regulate DgcA enzymatic activity in the low-micromolar range. Subsequent structure–activity studies on selected scaffolds revealed a remarkable diversity of modulatory behavior, including slight chemical substitutions that reverse the effects from allosteric enzyme inhibition to activation. The compounds identified represent new chemotypes and are potentially developable into chemical genetic tools for the dissection of c-di-GMP signaling networks and alteration of c-di-GMP-associated phenotypes. In sum, our studies underline the importance of detailed mechanism-of-action studies for inhibitors of c-di-GMP signaling and demonstrate the complex interplay between synthetic small molecules and the regulatory mechanisms that control the activity of diguanylate cyclases.
关键词： c-di-GMP,structure–activity relationships,FRET,diguanylate cyclase inhibitors,high-throughput screening
更新于2025-09-23 15:23:52
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[IEEE 2018 IEEE Biomedical Circuits and Systems Conference (BioCAS) - Cleveland, OH, USA (2018.10.17-2018.10.19)] 2018 IEEE Biomedical Circuits and Systems Conference (BioCAS) - Gaussian Monocycle Pulse Generator with Calibration Circuit for Breast Cancer Detection
摘要： Gaussian Monocycle Pulses (GMP) play a very important role in a radar-based painless breast cancer detection system. In order to guarantee the detection accuracy, it is necessary to stabilize the pulse width and the amplitude under the influence of the manufacturing variation of MOSFETs. Therefore, in this paper, the GMP generator with a calibration circuit is proposed. The calibration circuit for adjusting the delay time of each path is realized by MOS capacitor array. The proposed GMP generator has a center frequency of 5.5 GHz, -3dB bandwidth from 2.8 GHz to 9.1 GHz, and 498.6 μW power consumption.
关键词： Gaussian Monocycle Pulse (GMP),equivalent time sampling,breast cancer detection system,calibration circuit
更新于2025-09-23 15:23:52