The back-flip strategy, as demonstrated here with a peptidic protease inhibitor, provides a practical approach to engineering peptidic protein modulators in general and to mapping peptide–protein interaction surfaces.

The usefulness of the back-flip strategy is demonstrated by a rationally unpredictable improvement of a peptidic protease inhibitor following the loss of a peptide–protein polar interaction and an entropy penalty.

The high affinity of the new peptidic inhibitors to their target enzyme appears to be caused by their flexibility, enabling them to adapt to variable enzyme surfaces.