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A Sensitive in Vitro High-Throughput Screen To Identify Pan-filoviral Replication Inhibitors Targeting the VP35−NP Interface

A Sensitive in Vitro High-Throughput Screen To Identify Pan-filoviral Replication Inhibitors Targeting the VP35-NP InterfaceThe 2014 Ebola outbreak in West Africa, the largest outbreak on record, highlighted the need for novel approaches to therapeutics targeting Ebola virus (EBOV). Within the EBOV replication complex, the interaction between polymerase cofactor, viral protein 35 (VP35), and nucleoprotein (NP) is critical for viral RNA synthesis. We recently identified a peptide at the N-terminus of VP35 (termed NPBP) that is sufficient for interaction with NP and suppresses EBOV replication, suggesting that the NPBP binding pocket can serve as a potential drug target. Here we describe the development and validation of a sensitive high-throughput screen (HTS) using a fluorescence polarization assay. Initial hits from this HTS include the FDA-approved compound tolcapone, whose potency against EBOV infection was validated in a nonfluorescent secondary assay. High conservation of the NP-VP35 interface among filoviruses suggests that this assay has the capacity to identify pan-filoviral inhibitors for development as antivirals.

ACS Infect Dis. 2017 Mar 10;3(3):190-198.
doi: 10.1021/acsinfecdis.6b00209. Epub 2017 Feb 9.

 

© Copyright 2017 American Chemical Society.

  Liu G, Nash PJ, Johnson B, Pietzsch C, Ilagan MX, Bukreyev A, Basler CF, Bowlin TL, Moir DT, Leung DW, Amarasinghe GK.

Another SBC Highlight:

Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state
Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state

 

Nat Commun. 2017 Feb 13;8:14158. doi: 10.1038/ncomms14158.

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19-ID Pilatus Detector

 

SBC has implemented a Pilatus 3 X 6M detector into the User Program at beamline 19-ID. Data collected by our users has been of outstanding quality.

 

 

19-BM Robotic sample mounter available

 

A robot is available for use at beamline 19-BM. The sample dewar accommodates ten Unipuck magazines; pins must be 18mm in length and use either SSRL or ALS bases. Experienced users may now request remote access to 19-BM when applying for beamtime.

 

 

SBC Staff Hosting Changes

 

SBC staff are now available for User Support between the hours of 8:00am and 10:pm.

 

 

 

ALSO: Please Be Aware...!

 

APS requests the Experimental Safety Approval Form (ESAF) be submitted at least seven days prior to your scheduled beamtime.

 

Failure to submit your ESAF in advance may result in delaying the beginning of your experiment.

 

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Rapid Access Beamtime Available:

SBC Beamtime Request System

The on-line SBC Beamtime Request System allows users to view available beamtime on 19-ID and 19-BM, and to submit a request for rapid beamtime allocation.

Beamtime is available to the research community via a peer reviewed proposal system; it is supported by the U.S. Department of Energy, Office of Biological and Environmental Research.

Current Beamline Statistics:

APS PDB Depositions from BioSync
SBC Sector 19 2015 2016 2017 TOTAL
ID BM ID BM ID BM
PDB Depositions 263 32 169 28 68 12 5009

APS Publications Database:

Publications Total
SBC-CAT Publication List: 19-ID 1500
SBC-CAT Publication List: 19-BM 532
SBC-CAT Publication List: ALL
APS Publications Database

MCSG / APCF Announcements:

 

The Midwest Center for Structural Genomics (MCSG) is accepting applications for access to the MCSG User Resource.

 

MCSG's structure determination platform is well established, and combines technologies, robotics and expertise for gene cloning, protein production, and crystallization, as well as biochemical and biophysical characterization.

 

For further information, please contact Andrzej Joachimiak.

 

Future Meetings:

 

2017 APS/CNM User Meeting

May 8-11, 2017

Advanced Photon Source; Chicago; Illinois, USA

 

2017 Annual Meeting of the American Crystallographic Association

May 26-30, 2017

New Orleans; Louisiana, USA

 

10th annual CCP4 crystallographic school “From data collection to structure refinement and beyond”

June 19-26, 2017

Argonne National Laboratory; Chicago; Illinois, USA

 

SBC Beamline Phone Numbers:

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19-ID Beamline Control Station 630-252-9823
19-ID Beamline Cordless Phone 630-252-0569
19-ID Beamline Inside D-Hutch 630-252-1819
 
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19-BM Beamline Inside D-Hutch 630-252-1719