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Recorded on: Tuesday, January 24, 2017
Duration: 60 minutes
Featured Speaker: Douglas R. Davies, Senior Manager of Structural Biology, Beryllium Discovery Corp.

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This webinar will discuss the use of ligand-observe 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).

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Doug Davies Senior Manager Structural BiologyAbout Douglas R. Davies, Senior Manager of Structural Biology, Beryllium Discovery Corp.
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.



Ebolaviruses can cause severe haemorrhagic fever and was responsible for the 2013-2015 epidemic in West Africa, that resulted in over 11,000 deaths. Utilizing our fragments library, we employed saturation transfer difference nuclear magnetic resonance (STD NMR) spectroscopy to identify fragments that bound Filoviridae family members, Ebolavirus Zaire or Marburgvirus Lake Victoria nucleoprotein transcriptional cofactor VP30. Due to the adaptive tendencies of viral proteins, we identified fragments that bound one or both strains. To further interrogate the potential relationship of fragments with Ebola, additional STD NMR screening of Ebolavirus Zaire mutants was performed, determining the difference signal of select fragments with the active “unphosphorylated” and inactive “phosphorylated” mutants. A greater difference signal was observed with the active mutant which also included the Marburgvirus specific fragments. We believe that our findings and strategy lead towards a structure guided drug design path for more successful viral therapies in Ebola and can be applied to other pathogens.

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Probing Filoviridae: Identifying fragments that bind Ebolavirus and Marburgvirus

“We are excited to tell the story of one of the Beryllium collaborations on tuberculosis targets next week at PEGS.  As many in the anti-infectives therapeutics realm have realized, less than 10% of the disease-relevant proteome of mycobacterium tuberculosis has been successfully solved at the level of high dimensional 3-D structure.  Beryllium teamed up with the Seattle Structural Genomics Center for Infectious Disease (SSGCID) and others to address the question “Can we increase the breadth of structural insights within the disease-relevant protein group in the pathogen M. tuberculosis?”.   Accordingly, we demonstrate the utility of homologue rescue in this study- essentially applying a system for using surrogate sequences of the active sites from other mycobacteria – to establish a relationship between sequence identity and active site structural similarity between homologues.  This system applied to 179 potential tuberculosis drug targets increased the structural coverage more than 3-fold!”

MCL1 is one of the top-ten most amplified genes in all of human cancer and is vital to tumor development and cancer progression. Although MCL1 is a well-known cancer drug target, obtaining ligand-bound crystal structures has proven to be difficult.   In collaboration with the Broad Institute of MIT and Harvard, Scientists at Beryllium developed a robust crystallographic platform for MCL1 that uses a combination of fusion protein and sequence engineering.   Unlike previously available structures based on ligand dependent interactions, the new methods allow for systematic screening against MCL1 and opens the door to structure based drug design. 

Clifton et al describe their work in their recent PLOS One publication, where the first Apo and fragment bound x-ray structures of MCL1 are described. These structures provide important breakthroughs for MCL1 drug discovery by providing insight into conformational changes that occur upon ligand binding.  In addition, the approach allows for the observation of ligand binding to MCL1 in a non-ligand dependent manner.

About Beryllium:

Using our biology-first, target-centric approach and established platforms, we provide research services and engage in collaborations with commercial and academic partners.   Our teams of experienced scientists work closely with our clients to help manage and advance their goals by complementing their capabilities and resources.

Rempex Pharmaceuticals are developing Carbavance which contains the beta lactamase inhibitor RPX7009 combined with the beta-lactam antibiotic carbapenem as part of a treatment for hospitalized patients with serious bacterial infections. RPX7009 stops one of the primary defense mechanisms of the carbapenem-resistant Enterobacteriaceae which is reported by the CDC to be a urgent threat. By some estimates, carbapenem-resistant Enterobacteriaceae kill up to 50% of infected patients.  

Beryllium scientists helped determined the structure of the different complexes and this work contributed to the understanding of the binding and function of RPX7009.  The work was recently published in the Journal of Medicinal Chemistry.

This is an exciting time in the world of drug discovery. We are in the midst of shaping a new future, with externalization and collaboration at the core of the business and research models for a growing number of companies.  At Beryllium, our goal is to combine our expertise in structure-guided drug discovery with insights from functional biology to help our partners advance their research projects.

Akin to the pure, elemental vison of our name, we approach all of our partnerships with a keen focus on clarity and interaction transparency. Our aim is to build long-term partnerships with our clients.  Thus, our success relies, not just on the success of the science, but also on the success of the execution of the project.  We want our partners to think of us as extensions to their teams and not as “an external group we have a TC with once a week.”

Continue reading at the CORE Informatics blog

BEDFORD, Mass. – February 12, 2015 – In this week’s issue of Science, researchers at Gilead Sciences, Inc. (Nasdaq:GILD) and Beryllium reveal new details about how the hepatitis C virus (HCV) replicates its genome. HCV is estimated to affect 150-200 million people worldwide and is the major cause of liver transplantation in the US. HCV uses RNA as genetic material which must be replicated in order to propagate the viral infection. Appleby et al. determined high resolution X-ray crystal structures of the HCV polymerase during the process of RNA replication, shedding light on the replication complex after 15 years of speculation. These molecular snap-shots unveil the NS5B catalytic mechanism in successive steps from the opening of the fist-like polymerase through the rapid RNA polymerization stage known as elongation. “For the first time we can see at the atomic level how the HCV polymerase interacts with the genomic RNA template, replicating RNA, and nucleotide substrates,” said corresponding author Thomas Edwards of Beryllium.

Sofosbuvir acts during the elongation stage of HCV genomic replication, where the nucleotide triphosphate metabolite of the drug is incorporated into the growing RNA strand and terminates replication. The structural data presented by Appleby et al.demonstrate how the HCV polymerase recognizes sofosbuvir in a manner distinct from either native substrates or other nucleotide-based therapies.

“These structures advance our understanding of how an important member of the Flaviviridae family of viruses replicates genomic RNA,” said William Lee, Senior Vice President of Research at Gilead Sciences. “This information will be useful in identifying replication inhibitors of other pathogenic viruses in this family responsible for human diseases.”

Copies of the Science paper may be obtained from the AAAS Office of Public Programs. Please call +1-202-326-6440 or email

About Beryllium

Beryllium is shaping the future of collaborative drug discovery. Our proven teams of drug discovery professionals are passionate about unlocking the therapeutic potential of both genetically- and clinically-validated drug targets, as well as developing new therapeutic modalities. We work in partnership with our clients to address the most difficult scientific and business challenges facing drug discovery, and to ultimately enable transformational health care outcomes.

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