Abstract

In general, drug discovery in the therapeutic field of infectious disease has a stellar track record. And yet, subsets of pathogens, for example many classes of viruses other than HIV, HSV, influenza, and HCV, have been poorly addressed. In addition, the development of resistance remains a specter of great concern for almost all current chemotherapy directed against infectious diseases, including viruses. Within the viral lifecycle, capsid assembly stands out as a step occurring in all viruses, which has not been the subject of extensive drug discovery programs. Until recently, the common view of assembly was that all the necessary information for assembly was contained in the sequence of the viral protein, in other words, the capsid self-assembles. In the last few years, a body of data has opened new opportunities for antiviral pharmaceutical research. Evidence that host proteins may play catalytic or essential structural roles in viral capsid assembly suggests that these host proteins and their functions are novel targets for small molecule therapeutics. Here we review the current understanding of the capsid assembly process with emphasis on recent data that demonstrate the essential role of host proteins in capsid assembly. Furthermore, this dependency of assembly on host factors appears quite sensitive to small molecule intervention. Implications of this alternate mechanism of capsid assembly are also considered. For example, the dependency on host factors could impose a potent barrier to development of viral resistance to a host-targeted anti-capsid chemotherapeutic. Finally, we give specific examples of the current state of drug discovery programs that have focused on therapeutic inhibition of host-assisted viral capsid assembly.

Keywords: Host-catalyzed viral capsid formation, Whole-pathway drug discovery, Cell-free protein synthesis