A Brief Overview of Prosetta's Research Activities

Prosetta Biosciences, Inc is an early stage biotechnology company, founded to explore the potential of a Cell-Free Protein Synthesis System (CFPSS) for drug discovery. More specifically, the possibility that modified CFPSS might allow detection of highly druggable protein-protein interactions that have previously been undetected. Prosetta’s findings to date are summarized below with our investigation of crucial protein-protein interactions in virus cell biology. The capsid (the protein shell that protects the DNA or RNA genome of a virus), has long been believed to be made through self-assembly. CFPSS revealed a pathway by which complex machines of more than a dozen host proteins catalyze capsid formation via discrete assembly intermediates. Variations on the theme of this approach subsequently pursued by Prosetta scientists have allowed discovery of overlapping putative capsid assembly pathways for every family of virus investigated (to date, 17 of the 23 families of viruses known to cause human disease). Each of these previously unknown viral capsid protein-host protein interactions represent novel, potentially druggable, anti-viral targets, different in one fashion or another, for each family of disease-causing virus.

  • Before Prosetta’s discoveries: Classical teaching has been that viral capsid formation occurs through self assembly. Under that conceptual framework there is little to target other than the actual lattice of viral capsid proteins themselves.

  • A paradigm shift: Scientists in academic laboratories at UCSF and UW Seattle discovered that, contrary to conventional belief, a host factor-catalyzed pathway was essential for viral capsid formation.

  • Prosetta’s innovation: Small molecule screens of this newly discovered catalyzed capsid assembly pathway were established for ten families of human viral pathogens and used to identify a plethora of active pharmacophores.

  • Independent validation: These small molecules have proven robustly active against various live viruses as tested at academic and government laboratories around the world.

  • Recent conceptual extensions:

    • The concept of host assembly machines that catalyze the formation of multiprotein complexes (machines that build machines) has been extended to non-viral and non-infectious disease applications including the working hypothesis that disease-specific signaling complexes are constructed through action of similar assembly machines.

    • It appears that aberrant assembly machines are the basis for the pathological phenotype in multiple infectious and non-infectious diseases, so Prosetta’s approach should work more broadly.

    • The drugs we are discovering appear to preferentially target allosteric sites, the high-value drug targets that are very difficult to identify by conventional means.