Distance between the Basic Group of the Amino Acid Residue's Side Chain in Position P1of Trypsin Inhibitor CMTI-III and Asp189in the Substrate Pocket of Trypsin Has an Essential Influence on the Inhibitory Activity

Examples of Peptide–Peptoid Hybrid Serine Protease Inhibitors Based on the Trypsin Inhibitor SFTI‐1 with Complete Protease Resistance at the P1P1′ Reactive Site

“…Although the trypsin inhibitory activity of analogue 1 is two orders of magnitude lower than that determined for the native SFTI‐1, the result obtained is very promising. In our previous work on the trypsin inhibitor CMTI‐III,19 we have shown that requirements for the P1 position are very strict. In fact only analogues with Arg and Lys at this position exhibited a strong interaction with trypsin.…”

Analogues of trypsin inhibitor SFTI‐1 modified in the conserved P1′ position by synthetic or non‐proteinogenic amino acids retain their inhibitory activity

“…The introduction of other amino acids in this position of canonical inhibitors produced analogues without any affinity toward trypsin. A few years ago, we were able to demonstrate that this effect could be observed even when the amino acid residues differed from the proteinogenic ones by one methylene group in their side chains (Orn, Hly and Har)7. The affinity of inhibitors with Arg or Lys in the P 1 position toward other than trypsin‐like enzymes is significantly lower.…”

Modifications outside the proteinase binding loop in Cucurbita maxima trypsin inhibitor III (CMTI‐III) analogues change the binding energy with bovine β‐trypsin

“…Because of the small size (about 30 amino acid residues), compact structure (stabilized by three disulfide bridges) and strong inhibitory activity ( K a =10 11 –10 12 M −1 ) these inhibitors turned out to be very attractive templates for design of new serine proteinase inhibitors. In the last decade we synthesized both CMTI‐I and CMTI‐III and more than 30 selective trypsin, chymotrypsin and elastase inhibitors [3–9].…”