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.
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.
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.
- 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