scholarly journals Structural Insights into the Inhibition of Zika Virus NS2B-NS3 Protease by a Small-Molecule Inhibitor

Structure ◽  
2018 ◽  
Vol 26 (4) ◽  
pp. 555-564.e3 ◽  
Author(s):  
Yan Li ◽  
Zhenzhen Zhang ◽  
Wint Wint Phoo ◽  
Ying Ru Loh ◽  
Rong Li ◽  
...  
Keyword(s):  
Small Molecule ◽  
Zika Virus ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Ns3 Protease ◽  
Structural Insights

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 Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

2018 ◽  
Vol 430 (9) ◽  
pp. 1324-1335 ◽  
Author(s):  
Jianyun Huang ◽  
Raja Dey ◽  
Yufeng Wang ◽  
Jean Jakoncic ◽  
Igor Kurinov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Induced Fit ◽  
Molecule Inhibitor ◽  
Structural Insights

scholarly journals Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158

2020 ◽  
Vol 4 ◽  
pp. 100014 ◽  
Author(s):  
Yvonne Grobben ◽  
Joost C.M. Uitdehaag ◽  
Nicole Willemsen-Seegers ◽  
Werner W.A. Tabak ◽  
Jos de Man ◽  
...  
Keyword(s):  
Small Molecule ◽  
Ph Dependence ◽  
Small Molecule Inhibitor ◽  
Arginase 1 ◽  
Molecule Inhibitor ◽  
Structural Insights

scholarly journals A small molecule inhibitor of ER-to-cytosol protein dislocation exhibits anti-dengue and anti-Zika virus activity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jingjing Ruan ◽  
Hussin A. Rothan ◽  
Yongwang Zhong ◽  
Wenjing Yan ◽  
Mark J. Henderson ◽  
...  
Keyword(s):  
Small Molecule ◽  
Zika Virus ◽  
Small Molecule Inhibitor ◽  
Virus Activity ◽  
Molecule Inhibitor

scholarly journals Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4461-4469 ◽  
Author(s):  
Aibin Shi ◽  
Marcelo J. Murai ◽  
Shihan He ◽  
George Lund ◽  
Thomas Hartley ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Fusion Proteins ◽  
Small Molecule Inhibitor ◽  
Structural Basis ◽  
Protein Protein Interactions ◽  
Acute Leukemias ◽  
Protein Protein Interaction ◽  
Molecule Inhibitor ◽  
Structural Insights

Abstract Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a small-molecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin–MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-molecule inhibitor.

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