Rapid and Efficient Fragment Screening of Influenza and Ebola Viral Targets to Enable Novel Drug Discovery

This webinar will discuss the use of ligand-observed NMR techniques for rapid and efficient fragment screening of viral targets. Fragment screening was performed on two different viral proteins, an H1N1 Influenza A virus polymerase acid protein C-terminal domain (PA-CTD) and the Ebola virus matrix protein VP30 as part of a structural genomics consortium which targets infectious diseases. The influenza virus PA-CTD is part of the heterotrimeric viral RNA-dependent RNA polymerase involved in genome replication, whereas the Ebola virus VP30 protein is a phosphoprotein which associates with the nucleocapsid protein and is essential for viral transcription initiation.

In each case, the strategy was to target a protein-protein interface rather than an enzymatic active site. Interestingly, the majority of hits for the influenza A virus PA-CTD screen bind to a surface exposed site located near the viral RNA loading site rather than the expected PB1 N-terminus binding site which is a computational hot spot. Crystal structures of initial hits and follow on analogue-by-catalogue compounds were obtained. For the Ebola virus VP30 screen, VP30 was screened from both the 2013-2015 Zaire outbreak as well as the related Marburg virus VP30 in an effort to identify fragments which can target divergent viral VP30 strains. All of this work has been done as part of the Seattle Structural Genomics Center for Infectious Disease (SSGCID), a structural genomics consortium funded by the National Institute for Allergy and Infectious Diseases (NIAID).

Speaker

Douglas R. Davies

Over the past twenty years, some of Douglas’ work has focused on structural studies of functional nucleic acids and nucleic-acid modifying enzymes. His graduate thesis work at the University of Wisconsin-Madison involved the first structures of Tn5transposase. As a postdoctoral fellow at the University of Washington, Douglas studied the DNA repair enzyme Tyrosyl DNA Phosphodiersterase (Tdp1), elucidating the first crystal structures and verifying the proposed mechanism of action. During the past 10 years at Beryllium, he has applied these experiences to a number of DNA aptamer diagnostics and potential therapeutics (SOMAmers) as well as DNA Polymerase C from Geobacillus kaustophilus. Douglas is the lead crystallographer for 77 crystal structures in the Protein Data Bank and has published 28 peer-reviewed journal articles.

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