Resisting degradation by human elastase: Commonality of design features shared by ‘canonical’ plant and bacterial macrocyclic protease inhibitor scaffolds

A previously unexplained difference in the resistance to enzymatic hydrolysis of 11-mer Bowman–Birk-type inhibitors of human leukocyte elastase that differ in P1 is found to correlate with the strength of a particular intramolecular hydrogen bond within the inhibitor. This transannular hydrogen bond stabilizes the side chain of the conserved P2 Thr in a ‘canonical’ +60°-rotamer χ1 conformation and thereby directs it for a close interaction with the enzyme’s catalytic His. As the implications of this NMR analysis are neither limited to this macrocyclic scaffold derived from plant proteins nor to a particular serine protease, we present a unified analysis with inhibitory bacterial depsipeptides of 7–12 residues in length that share key design features for which we propose communal functional explanations.

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