Prosetta's Science

 

An Ubiquitous yet Unrecognized Layer of Biology

Prosetta is unique in recognizing and taking advantage of the existence of cellular “assembly machines”, which Prosetta has demonstrated to be a promising and completely unexplored class of drug target. It has long been known that many proteins act as members of complexes. Formation of complexes has been viewed as spontaneous, the individual proteins simply finding and binding one another. Starting with work on viruses, Prosetta has demonstrated that a set of large, dynamic protein complexes exists that catalyzes the formation of other complexes. Hence the name “assembly machines”.

Assembly machines appear to be critical points of regulation modified by a wide variety of disease states. Viruses and other disease states subtly change the structure of one or more assembly machines such that the normal and aberrant forms of an assembly machine can be distinguished. Prosetta has identified compounds that specifically recognize the aberrant forms and, via allosteric effects, prevent or reverse effects of the disease. 

 

Prosetta website graphic DNARNAetc 1-20-17[1].jpg

 

What led Prosetta to assembly machines, and why are they good targets?

Prosetta’s recognition of the significance of assembly events in human diseases originated with work done by co-CEO Vishu Lingappa while a faculty member at the University of California San Francisco. This work revealed that, rather than assembling spontaneously from their constituent proteins and nucleic acids as was believed at the time, the assembly of viral particles was actually actively catalyzed by proteins of the infected cell. Prosetta is based upon the implications of being able to target the host factors involved in assembly, and the tremendous advantages that this allows.

Catalyzed viral assembly has proven highly druggable. Screening at Prosetta has identified drug-like chemical compounds for 20 of the 23 viral families that exist. And, as Prosetta has learned about the host proteins that catalyze the assembly of the viruses, the story has gotten even more promising. Assembly is catalyzed by large, dynamic complexes of host proteins that Prosetta calls “assembly machines”. These machines exist in uninfected cells as well, but the virus modifies them to serve its own purposes.

Notably, only a small fraction of each host protein that is part of an assembly machine participates at any one time. These two properties – a unique structure in infected cells and small fraction of each constituent protein – make assembly machines highly advantageous targets for drugs. Because only a small fraction of each host protein is involved, they can be targeted without compromising any other functions that protein has within the cell, minimizing toxicity to the host. And, because host – rather than viral – proteins are the targets, the development of resistance to the drug is rare. Over several years of testing, Prosetta has rarely seen resistance develop to one of its drugs.

Prosetta’s approach is not limited to diseases caused by viruses. In a true “eureka” moment, it became apparent that what we had done with our viral work was to identify a collection of central control points within the cell. We reasoned that viral infection might not be the only “insult” that modifies these control points and the assembly machines that form them. This appears to be the case.  Drugs identified by Prosetta in viral screens have proven to work in cellular models of non-viral diseases such as Alzheimers and Parkinsons Diseases, amyotrophic lateral schlerosis, schizophrenia and various bacterial and parasitic infections. Several compounds have broad and robust anticancer activity. From our virally identified hit compounds we have assembled a collection of approximately 300 molecules that we refer to as our “Hitfinder Collection” and routinely use to start new projects. So far, we have used it in 24 unrelated cases, and it has yielded one or more developable hits in every instance.

Prosetta now finds itself with an embarrassment of riches, and seeks partners interested in positioning themselves for this next generation of drug targets.

 

Assembly in biology

Cells are replete (filled with, chock full of) with large protein complexes that perform fundamental roles like replicating and repairing the genetic material and making, folding and degrading proteins. Other less benign protein complexes like virus particles are also often present, resulting in human disease.

The idea of self assembly has deeply embedded itself throughout biology over the past 50 years. Because large protein complexes like viruses could be made to assemble from their purified components in the test tube, it was assumed that they did so in the cell. The reality has proven much more complicated. Large protein complexes like ribosomes are actively assembled in a highly choreographed, assembly line manner performed by cellular components dedicated to the purpose. In fact, the idea of assembly now pervades biology, and (many) cellular components once thought to act alone are now recognized to act as pieces in large protein assemblies. It now appears that assisted assembly will be ubiquitous. This level of cellular organization is only now beginning to come into focus, and its control is almost completely unexplored.

Prosetta has discovered that assembly of protein complexes is even more common than thought, and has detected a machinery devoted to it. Prosetta’s work has revealed that this machinery – which it calls “assembly machines” - acts at crucial regulatory points that are modified in human diseases. These machines have proven to be highly druggable targets. Critically, their composition changes between normal and diseased states, enabling the selective targeting of machines unique to the diseased states. Prosetta’s unusual approach uniquely positions it to take advantage of this new and attractive class of target, and so far has identified small molecules active against infections, cancer, and CNS diseases.