Directed evolution and de novo design for improved pathogen-targeting protein drugs

Abstract

Infectious diseases continue to claim millions of lives, and protein design with Rosetta is quickly becoming a contributor to the fight against these diseases. My dissertation has focused on leveraging recently developed high-throughput synthesis and screening technologies to improve existing designed proteins for use as pathogen-targeting drugs as well as to develop new design methods for infectious disease targets. First, I present my effort to develop techniques to improve two existing influenza-targeting proteins into viable protein drugs, in terms of higher stability and stronger influenza neutralization and how, with collaborators, I developed one of these improved proteins into the first designed protein to ever cure an infectious disease in an animal model. Second, I present my efforts to develop a new protein design method that incorporates existing known structural motifs into fully de novo protein scaffolds at massive scale, and use this method to test the hypothesis that structure-based design can stabilize a malaria surface epitope in order to build a better malaria vaccine. It is hoped that these contributions will bring designed protein drugs closer to pharmaceutical relevance and help reduce the burden of infectious disease worldwide.