Case Studies

Dyax Corp

Dyax Corp. wanted to understand how their antibody (DX-2930) was inhibiting a protease involved in hereditary angioedema (HAE).

Dynax Corp Case Study

EXPERIENCE / INSIGHT:

Beryllium generated recombinant human plasma kallikrein (pKal) for assays and crystallization using baculovirus infected insect cells with secreted expression and native refolding. Complex formation with the Dyax provided Fab of DX-2930 was used to determine a proper stoichiometric ratio, essential for success in crystallography. To understand the interaction between DX-2930 and pKal with atomic resolution, we crystallized the Fab portion of DX-2930 both alone and in a complex with a deglycosylated variant of the human pKal catalytic domain.

SOLUTION:

Results clearly showed the molecular details of the epitope/paratope interactions, thus providing a biological rational to how the antibody is functioning. In the Fab alone structure, the CDR loops are disordered, thus suggesting the antibody-antigen interaction is not preformed, thus the interaction between the two is an induced fit. DX-2930 functions by specifically blocking the active site of pKal, thus acting similar to the Serpin C1 inhibitor that is deficient in individuals with hereditary angioedema.

Gilead Sciences

Collaboration with Pharmasset (Gilead acquisition)

Pharmasset required a partner to determine the mechanism of action of an important new oral hepatitis C virus (HCV) drug to understand how it would synergistically interact with other drugs on the market and in development.

EXPERIENCE/INSIGHT:

Beryllium set out to obtain structures of HCV NS5B polymerase bound to RNA and incoming nucleotides to understand:

  •  Structural changes required for activation of the polymerase.
  • Binding of native substrates and nucleotide analog inhibitors (NAI) to active NS5B polymerase complexes.

SOLUTION:

Beryllium determined a series of crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis.

  HCV Case Study Beryllium Case Study

  • The crystal structures capture a number of key steps throughout the catalytic pathway including the two slow steps and have allowed Beryllium to propose a more complete catalytic pathway for HCV polymerase.
  • Beryllium obtained elongation phase ternary complexes with NAIs including the metabolite of the FDA approved drug sofosbuvir. These structures showed differences in the active site which demonstrated why sofosbuvir is distinct from native substrates or other nucleotide analog inhibitors in development

The Broad Institute

Structure-guided Drug Discovery

COLLABORATION

The Eli and Edythe L. Broad Institute of Harvard and MIT is unlocking the molecular basis of many diseases, including cancer, diabetes and other inherited disorders. After years of generating many disease targets, the Broad Institute sought out Beryllium as a partner to help them translate their discoveries into tractable drug targets.

EXPERIENCE

Beryllium’s experience working to elucidate hundreds of infectious disease targets and providing over 675 structures for the Seattle Structural Genomics Center for Infectious Disease (SSGCID) provided the Broad Institute with the assurance that Beryllium can deliver consistent answers about protein structure and function, and can also effectively manage project portfolios, both scientifically and financially.

INSIGHT

The Broad Institute and Beryllium combined forces to determine the functional characteristics of hundreds of targets, including PCSK9 and MCL1, utilizing Beryllium’s in-house structural biology capabilities, as well as insights from the Beryllium drug discovery team and advisory board.

SOLUTION

The goal of this partnership is to translate the wealth of disease knowledge generated at the Broad Institute into revolutionary new medicines that will significantly improve human health.

Center for Infectious Disease Research

SSGCID wanted to use fragment based screening to identify starting points for novel anti flu drugs.

SSGCID wanted to use fragment based screening to identify starting points for novel anti flu drugs.

EXPERIENCE/INSIGHT:

Beryllium performed fragment screening against the polymerase acidic (PA) subunit of the heterotrimeric PA-PB1-PB2 by STDNMR to identify fragments which bind to H1N1 PA-CTD and target a protein-protein interface:

  • Screened the Fragments of Life library consisting of 1080 compounds
  • 139 putative hits
  • Top 50 hits were examined in singleton experiments yielding 39 confirmed hits
  • 9 crystal structures of original and elaborated fragment hits

SOLUTION:

A number of fragments were identified by STD-NMR which were shown via x-ray crystallography to bind to a novel, distal yet highly conserved hydrophobic pocket on PA-CTD. One chemical series bound a novel, conserved (in flu A) hydrophobic surface binding site near the vRNA loading site. Although we expected many of the hits to bind to the PB1 binding site which is a hot spot for in silico binding and conformational change, we obtained a series of chlorophenyl compounds which bound to a surface site distal to the PB1 binding site. Interestingly, this site is located in close proximity to the viral RNA (vRNA) loading site and a species specific differential loop.

UCB Pharma

Small-molecule Drug Discovery

COLLABORATION

Beryllium has partnered with UCB to develop first-in-class, small-molecule drugs for disease indications in which the current standard of care is limited to expensive injectable drugs. During this ongoing six-year relationship, the joint discovery team has made significant scientific breakthroughs that have helped redefine the druggable genome.

EXPERIENCE & INSIGHT

Beryllium’s expertise in structural biology, proteins and allosteric interactions, combined with the team’s deep understanding of antibody and epitope mapping, is providing transformative insight into well-validated drug targets that are currently limited to protein or antibody therapeutics.

SOLUTION

This collaboration has made amenable a multibillion-dollar drug target class to small-molecule ligands that are currently progressing toward clinical development. This success and others stemming from this partnership have formed the foundation for an expanded project scope and an equity investment in Beryllium.

Protein Expression and Crystallization of A Multi-Protein Complex

Calcineurin Complex Triple Expression Construct

Infection of insect cells with Baculovirus encoding the Calcineurin complex in presence of FK-506Infection of insect cells with Baculovirus

Co-purification of Calcineurin Complex in Presence of FK-506

Co-purification of Calcineurin Complex in Presence of FK-506

Crystallization and Structure Determination of Calcineurin Complex

1.85Å structure

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