scholarly journals Identification and Biochemical Characterization of Small-Molecule Inhibitors of West Nile Virus Serine Protease by a High-Throughput Screen

2009 ◽  
Vol 53 (1) ◽  
pp. 341-341 ◽  
Author(s):  
Niklaus H. Mueller ◽  
Nagarajan Pattabiraman ◽  
Camilo Ansarah-Sobrinho ◽  
Prasanth Viswanathan ◽  
Theodore C. Pierson ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Serine Protease ◽  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
Biochemical Characterization ◽  
High Throughput Screen ◽  
West Nile

Characterization of Small Molecule Inhibitors of West Nile Virus NS3 Serine Protease

2008 ◽  
Vol 78 (2) ◽  
pp. A50-A50
Author(s):  
P VISWANATHAN ◽  
N MUELLER ◽  
N PATTABIRAMAN ◽  
K LEE ◽  
G CUNY ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Serine Protease ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
West Nile

Discovery of small molecule inhibitors of West Nile virus using a high-throughput sub-genomic replicon screen

2006 ◽  
Vol 70 (2) ◽  
pp. 39-50 ◽  
Author(s):  
B GU ◽  
S OUZUNOV ◽  
L WANG ◽  
P MASON ◽  
N BOURNE ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
West Nile

scholarly journals Identification and Biochemical Characterization of Small-Molecule Inhibitors of West Nile Virus Serine Protease by a High-Throughput Screen

2008 ◽  
Vol 52 (9) ◽  
pp. 3385-3393 ◽  
Author(s):  
Niklaus H. Mueller ◽  
Nagarajan Pattabiraman ◽  
Camilo Ansarah-Sobrinho ◽  
Prasanth Viswanathan ◽  
Theodore C. Pierson ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Dengue Virus ◽  
Serine Protease ◽  
Small Molecule ◽  
High Throughput ◽  
The West ◽  
West Nile ◽  
Polyprotein Processing ◽  
Chemical Structures ◽  
High Throughput Screening Assay

ABSTRACT West Nile virus and dengue virus are mosquito-borne flaviviruses that cause a large number of human infections each year. No vaccines or chemotherapeutics are currently available. These viruses encode a serine protease that is essential for polyprotein processing, a required step in the viral replication cycle. In this study, a high-throughput screening assay for the West Nile virus protease was employed to screen ∼32,000 small-molecule compounds for identification of inhibitors. Lead inhibitor compounds with three distinct core chemical structures (1 to 3) were identified. In a secondary screening of selected compounds, two compounds, belonging to the 8-hydroxyquinoline family (compounds A and B) and containing core structure 1, were identified as potent inhibitors of the West Nile virus protease, with K i values of 3.2 ± 0.3 μM and 3.4 ± 0.6 μM, respectively. These compounds inhibited the dengue virus type 2 protease with K i values of 28.6 ± 5.1 μM and 30.2 ± 8.6 μM, respectively, showing some selectivity in the inhibition of these viral proteases. However, the compounds show no inhibition of cellular serine proteases, trypsin, or factor Xa. Kinetic analysis and molecular docking of compound B onto the known crystal structure of the West Nile virus protease indicate that the inhibitor binds in the substrate-binding cleft. Furthermore, compound B was capable of inhibiting West Nile virus RNA replication in cultured Vero cells (50% effective concentration, 1.4 ± 0.4 μM; selectivity index, 100), presumably by inhibition of polyprotein processing.

scholarly journals Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease

2012 ◽  
Vol 94 (1) ◽  
pp. 18-24 ◽  
Author(s):  
Manolya Ezgimen ◽  
Huiguo Lai ◽  
Niklaus H. Mueller ◽  
Kyungae Lee ◽  
Gregory Cuny ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Serine Protease ◽  
West Nile

scholarly journals Cell‐based high‐throughput screen for small molecule inhibitors of Bax translocation

2018 ◽  
Vol 23 (3) ◽  
pp. 1784-1797 ◽  
Author(s):  
Kelvin Kai‐Wan Hui ◽  
Chesarahmia Dojo Soeandy ◽  
Stephano Chang ◽  
Frederick S. Vizeacoumar ◽  
Thomas Sun ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
High Throughput Screen

scholarly journals Small Molecule Inhibitors of Phospholipase C from a Novel High-throughput Screen

2013 ◽  
Vol 288 (8) ◽  
pp. 5840-5848 ◽  
Author(s):  
Weigang Huang ◽  
Matthew Barrett ◽  
Nicole Hajicek ◽  
Stephanie Hicks ◽  
T. Kendall Harden ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
High Throughput Screen

scholarly journals A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity

2010 ◽  
Vol 4 (4) ◽  
pp. e659 ◽  
Author(s):  
Elizabeth R. Sharlow ◽  
Todd A. Lyda ◽  
Heidi C. Dodson ◽  
Gabriela Mustata ◽  
Meredith T. Morris ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
High Throughput Screen ◽  
Antiparasitic Activity

scholarly journals A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN)

PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0210525 ◽  
Author(s):  
Joshua A. Sommers ◽  
Tomasz Kulikowicz ◽  
Deborah L. Croteau ◽  
Thomas Dexheimer ◽  
Dorjbal Dorjsuren ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
Werner Syndrome ◽  
High Throughput Screen

scholarly journals Small-Molecule Inhibitors of toxT Expression in Vibrio cholerae

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Rebecca Anthouard ◽  
Victor J. DiRita
Keyword(s):  
Cholera Toxin ◽  
Vibrio Cholerae ◽  
Small Molecule ◽  
High Throughput ◽  
Small Molecule Inhibitors ◽  
Severe Disease ◽  
Virulence Gene ◽  
High Throughput Screen ◽  
Content Type ◽  
Oral Rehydration

ABSTRACTVibrio cholerae, a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production byV. choleraeis tightly regulated by the virulence cascade. In this study, we designed and carried out a high-throughput chemical genetic screen to identify inhibitors of the virulence cascade. We identified three compounds, which we named toxtazin A and toxtazin B and Bʹ, representing two novel classes oftoxTtranscription inhibitors. All three compounds reduce production of both CT and the toxin-coregulated pilus (TCP), an important colonization factor. We present evidence that toxtazin A works at the level of thetoxTpromoter and that toxtazins B and Bʹ work at the level of thetcpPpromoter. Treatment with toxtazin B results in a 100-fold reduction in colonization in an infant mouse model of infection, though toxtazin A did not reduce colonization at the concentrations tested. These results add to the growing body of literature indicating that small-molecule inhibitors of virulence genes could be developed to treat infections, as alternatives to antibiotics become increasingly needed.IMPORTANCEV. choleraecaused more than 580,000 infections worldwide in 2011 alone (WHO, Wkly. Epidemiol. Rec. 87:289-304, 2012). Cholera is treated with an oral rehydration therapy consisting of water, glucose, and electrolytes. However, asV. choleraeis transmitted via contaminated water, treatment can be difficult for communities whose water source is contaminated. In this study, we address the need for new therapeutic approaches by targeting the production of the main virulence factor, cholera toxin (CT). The high-throughput screen presented here led to the identification of two novel classes of inhibitors of the virulence cascade inV. cholerae, toxtazin A and toxtazins B and Bʹ. We demonstrate that (i) small-molecule inhibitors of virulence gene production can be identified in a high-throughput screen, (ii) targeting virulence gene production is an effective therapeutic strategy, and (iii) small-molecule inhibitors can uncover unknown layers of gene regulation, even in well-studied regulatory cascades.

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