The Prosetta Platform

 

Prosetta’s approach begins with cell free protein synthesis in whole cell extracts. This approach replicates the complexity of events within the cell in a way that assays with purified components cannot, and allows for the possibility of unanticipated druggable activities and events. Prosetta has found that events very early in the lifetimes of proteins often determine their function. In particular, proteins that play central roles in many human illnesses, such as those that form viral capsids or participate in neurodegenerative diseases, are the substrates for catalyzed assembly reactions during or shortly after their synthesis. These assembly reactions have proven excellent targets for drugs.

With intense and prolonged effort, Prosetta has optimized its proprietary cell free protein synthesis system to serve as an assay to detect these assembly reactions. A protein synthesis reaction is programmed with with a message related to the disease of interest, and compounds that interfere with the assembly reaction identified. This approach is greatly accelerated by the use of Prosetta’s Hit Finder Collection, a library of fewer than 400 molecules that is the result of many years of work by Prosetta to identify a small set of molecules that target a finite set of multi protein complexes that Prosetta calls “assembly machines”. To date, in 24 tries with unrelated diseases, this library has never failed to provide at least two chemically tractable starting points.

The initial hits recognize the form of assembly machine present in healthy cells. Prosetta uses a combination of classic medicinal chemistry and proprietary drug resin affinity chromatography to develop the hit into a molecule that recognizes the related yet subtly different version of the assembly machine specific to diseased cells. What results is a full spectrum of allosteric modulators, ranging from strongly activating to strongly inactivating.

Having developed the Hitfinder Collection, Prosetta now often skips the initial phase of cell free protein synthesis, and simply uses the Hitfinder Collection in cell-based screens. This approach has led to our CNS and oncology programs, and offers the potential for vastly accelerated conventional or exploratory screening, as well as the use of complex, highly informative assays – such as proteomics or whole tissue microscopy - that cannot be used in screens with large compound libraries. Why screen a million molecules when you can screen 300 with far greater resolution?