De novo design of protein binders as functional therapeutics

Thesis (Ph.D.)--University of Washington, 2023 ; De novo design of protein binding proteins (minibinders) with target structure information alone remains a grand challenge. A general computational design framework includes (1) generation of binder backbones, (2) sequence design and side-chain refinement, (3) resampling, and (4) prediction of binding and evaluation of the minibinders as a monomer. In Chapter 1, I review the improved computational minibinder design method I have contributed to develop. With these cutting-edge pipelines, I describe two strategies of applying designed minibinders as novel functional therapeutics: in Chapter 2, I report the design of minibinder antagonists as immune modulator for cytokine storm; in Chapter 3, I report the design of endocytosis ligands for target degradation and signaling amplification. Overall, the minibinder is a brand-new drug modality/platform with advantages of ultra-stability, high-specificity, robust production, and modularity. The work described indicate the great potential of the minibinder to bridge the gap of existing therapeutics and revolutionize the future of protein drug development.