Protein-based therapeutics are part of the next-generation arsenal of drugs against oncoprotein Myc. Max is a transcription factor that heterodimerizes with Myc and regulates Myc activity. The Myc/Max heterodimer binds to the E-box DNA target and can upregulate genes in uncontrolled manner. This Myc/Max:E-box network is involved in &gt;50% of all cancers. The E-box also governs transcription of plasminogen activator inhibitor 1, which is critical in the development of asthma, the most common chronic disease among children. We used rational design and phage-assisted continuous evolution (PACE) on our designed minimalist protein ME47 that suppresses tumor growth in cell culture and in mouse xenograft models. PACE uncovered unpredictable mutations; further design improved protein dimerization and stability. Our proteins demonstrate the power and utility of combining rational design and continuous evolution toward development of potential protein drugs with robust structure and DNA-binding function.

Rational design & continuous evolution of minimalist proteins that target the E-box DNA site

ACS Fall 2020 Virtual Meeting

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