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This protocol describes HyCoSuL, an approach that uses tetrapeptides containing natural and >100 unnatural amino acids to screen for protease substrate specificity and to engineer highly active and selective substrates and activity-based probes.
Selection of molecular targets based on disease understanding is a dominant paradigm in drug discovery. We argue that a focus on classes of targets with central roles in biology provides a complementary approach that has higher quality outcomes in early discovery efforts.