Host-Catalyzed Capsid Assembly Makes Possible Pan-Respiratory Viral Therapeutics
Prosetta’s central insight has been the discovery of a set of transient multiprotein complexes, that we term assembly machines, which normally perform assembly functions for the host. Upon viral infection, a subset of the cell’s normal assembly machines are modified by the virus in a way that renders them aberrant in structure and function. These modified, aberrant assembly machines no longer serve the cell, but instead serve the virus by assembling its capsid.
Aberrant assembly machines have several properties that make them highly advantageous targets for antiviral drugs. One is that they are present only in infected cells, potentially allowing for drugs very specific to the infected state. In addition, they are composed solely of host proteins, thus avoiding the development of resistance that occurs when viral proteins, whose resistance mutations are rapidly selected, are targeted.
While most virally-modified assembly machines are specific for a given viral family, Prosetta has found that a subset appears to be shared by several viral families, thus allowing the possibility of drugs with broad antiviral activity. Specifically, using infectious virus in cell culture, we have discovered a number of drug-like small molecule chemotypes that target a structural feature shared by assembly machines responsible for capsid formation in six families of viruses that cause major human respiratory diseases (influenza, rhinovirus, adenovirus, respiratory syncytial virus, coronavirus and cytomegalovirus). Prosetta is advancing two of these chemotypes to serve as novel therapeutics that would allow treatment of viral respiratory diseases without making a specific diagnosis. Such therapeutics may also provide valuable new opportunities to short-circuit respiratory virus-triggered exacerbations of asthma and chronic obstructive pulmonary disease, two very common medical complications.