Abstract Efficiency and substrate specificity of proteases in the Potyviridae family have not been comprehensively profiled. Here we develop a model that learns co-evolutionary features to accurately predict and experimentally validate protease performance at single amino-acid resolution. We identify and engineer several proteases that perform better than the commercially available tobacco etch virus protease. To demonstrate the resolving power of our methods, we engineer protease crosstalk to selectively trigger a synthetic cell-death program in human cells.
Suan et al. (2026) studied this question.