Necrosulfonamide inhibits necroptosis by selectively targeting the mixed lineage kinase domain-like protein

MedChemComm ◽  
2014 ◽  
Vol 5 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Daohong Liao ◽  
Liming Sun ◽  
Weilong Liu ◽  
Sudan He ◽  
Xiaodong Wang ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Kinase Domain ◽  
Small Molecule Inhibitor ◽  
Mixed Lineage Kinase ◽  
Sar Studies ◽  
Structure Activity ◽  
Molecule Inhibitor ◽  
Smac Mimetic

Through high-throughput screening of 200 000 compounds and subsequent structure–activity relationship (SAR) studies we identified necrosulfonamide (NSA) as a potent small molecule inhibitor for necroptosis, induced by a combination of TNF-a, Smac mimetic, and z-VAD-fmk (T/S/Z).

scholarly journals A Novel Dengue Virus Inhibitor, BP13944, Discovered by High-Throughput Screening with Dengue Virus Replicon Cells Selects for Resistance in the Viral NS2B/NS3 Protease

2013 ◽  
Vol 58 (1) ◽  
pp. 110-119 ◽  
Author(s):  
Chi-Chen Yang ◽  
Han-Shu Hu ◽  
Ren-Huang Wu ◽  
Szu-Huei Wu ◽  
Shiow-Ju Lee ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitor ◽  
Current Treatment ◽  
Stable Cell Line ◽  
Epidemic Disease ◽  
Molecule Inhibitor ◽  
Ns3 Protease

ABSTRACTDengue virus (DENV) causes disease globally, resulting in an estimated 25 to 100 million new infections per year. No effective DENV vaccine is available, and the current treatment is only supportive. Thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. In the present study, we identified a potential small-molecule inhibitor, BP13944, via high-throughput screening (HTS) of 60,000 compounds using a stable cell line harboring an efficient luciferase replicon of DENV serotype 2 (DENV-2). BP13944 reduced the expression of the DENV replicon reporter in cells, showing a 50% effective concentration (EC50) of 1.03 ± 0.09 μM. Without detectable cytotoxicity, the compound inhibited replication or viral RNA synthesis in all four serotypes of DENV but not in Japanese encephalitis virus (JEV). Sequencing analyses of several individual clones derived from BP13944-resistant RNAs purified from cells harboring the DENV-2 replicon revealed a consensus amino acid substitution (E66G) in the region of the NS3 protease domain. Introduction of E66G into the DENV replicon, an infectious DENV cDNA clone, and recombinant NS2B/NS3 protease constructs conferred 15.2-, 17.2-, and 3.1-fold resistance to BP13944, respectively. Our results identify an effective small-molecule inhibitor, BP13944, which likely targets the DENV NS3 protease. BP13944 could be considered part of a more effective treatment regime for inhibiting DENV in the future.

scholarly journals High-Throughput Screening Reveals a Small-Molecule Inhibitor of the Renal Outer Medullary Potassium Channel and Kir7.1

2009 ◽  
Vol 76 (5) ◽  
pp. 1094-1103 ◽  
Author(s):  
L. Michelle Lewis ◽  
Gautam Bhave ◽  
Brian A. Chauder ◽  
Sreedatta Banerjee ◽  
Katharina A. Lornsen ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Identification of Small Molecule Modulators of Diguanylate Cyclase by FRET-based High-Throughput-Screening

2018 ◽  
Author(s):  
Matthias Christen ◽  
Cassandra Kamischke ◽  
Hemantha D. Kulasekara ◽  
Kathleen C. Olivas ◽  
Bridget R. Kulasekara ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
High Throughput ◽  
Biofilm Formation ◽  
High Throughput Screening ◽  
Diguanylate Cyclase ◽  
Chronic Infections ◽  
Structure Activity ◽  
Diguanylate Cyclases ◽  
Small Molecule Modulators

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 may make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c-di-GMP, may be attractive drug targets to control biofilm formation that is part of chronic infections. In this paper, 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 7 small molecules that in the low µM range regulate DgcA enzymatic activity. Subsequent structure activity studies on selected scaffolds revealed a remarkable diversity of modulatory behaviors, including slight chemical substitutions that revert the effects from allosteric enzyme inhibition to activation. The compounds identified represent novel 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 for 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.

scholarly journals Structure–activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1

2010 ◽  
Vol 8 (19) ◽  
pp. 4281 ◽  
Author(s):  
Anders Bach ◽  
Nicolai Stuhr-Hansen ◽  
Thor S. Thorsen ◽  
Nicolai Bork ◽  
Irina S. Moreira ◽  
...  
Keyword(s):  
Small Molecule ◽  
Pdz Domain ◽  
Small Molecule Inhibitor ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Molecule Inhibitor
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