Abstract
Proteases are enzymes that cleave other proteins at defined locations. Such enzymes are attractive as therapeutics, but reprogramming them to selectively target a specific substrate is challenging. The natural substrates of botulinum neurotoxin (BoNT) proteases, including the enzyme marketed as Botox, are proteins involved in the formation and release of vesicles in neurons. These enzymes are examples of clinically used proteases that researchers have attempted to repurpose with varying degrees of success. Now researchers have used directed evolution to successfully repurpose enzymes in this class, potentially opening a route to develop new anticancer drugs. David R. Liu of Broad Institute of MIT and Harvard and the Howard Hughes Medical Institute, Min Dong of Harvard Medical School, and coworkers have now used a directed evolution method called phage-assisted continuous evolution (PACE) to reprogram the specificity of BoNT proteases so they target proteins other than their natural substrates ( Science 2021, DOI:
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