Trypsin, chymotrypsin, cathepsin protease inhibitors

One goal in the design of an inhibitor is specificity. Often this is a considerable challenge since physiological systems contain a number of closely related proteases. For example, there are at least four chymo-trypsin-like enzymes in humans. These include pancreatic chymotrypsin, cathepsin G, and two mast cell proteases (the human enzymes have not been characterized yet, but two are found in rats). All of these enzymes... 

None of the protein inhibitors of NE presented in this chapter are protease specific. They all inhibit more than one protease, but they are protease class specific (Table 5). For example, ai-PI, SLPI, and eglin c are serine-protease inhibitors and inhibit trypsin, chymotrypsin, and cathepsin G in addition to NE. However, ai-PI is an inhibitor of neutrophil PR3, whereas SLPI and eglin c are only very weak inhibitors of PR3 [40]. By contrast, elafin, which shares 38% homology with the C-terminal domain of SLPI, does inhibit PR3. A strong selectivity for NE is important to reduce toxicity resulting from interference of the inhibitor with other proteolytic processes. 

Selected entries from Methods in Enzymology [vol, page(s)] Sulfonylation reaction, 11, 706 reaction kinetics, 11, 707 second-order rate constants for inactivation of chymotrypsin, trypsin, and acetylcholine esterase by PMSE and related sulfonylat-ing agents, 11, 707 reactivation of PMS-chymotrypsin, 11, 710 as inhibitor [of calcium-activated factor, 80, 674 of cathepsin G, 80, 565 of crayfish trypsin, 80, 639 of elastase, 80, 587 of pro-lylcarboxypeptidase, 80, 465 of protease Re, 80, 691 of protease So, 80, 695 of protein C, 80, 329] proteolysis, 76, 7. 

Inhibitor peptides low molecular mass oligopeptide-fatty acid compounds of microbial origin which irreversibly inactivate plant and animal proteases. The inhibition is stoichiometric, i.e. 1 molecule I.p. inhibits 1 molecule enzyme. Examples are Leupeptin [acetyl-(or propionyl-)L-Leu-L-Leu-arginal the L-leu-cine can also be replaced by L-isovaline or L-valine], from Streptomyces species, inhibits cathepsin B, papain, trypsin, plasmin and cathepsin D, the effectiveness of the inhibition decreasing in that order. Pepsta-tin (isovaleryl-L-Val-L-Val-P-hydroxy-Y-NH2- -CH3-heptanoyl-L-Ala-P-hydroxy-Y-NHj-e-heptanoic acid), from actinomycetes, inhibits pepsin and cathepsin D. Chymostatin inhibits all known chymotrypsin types, cathepsin A, B, and D and papain. Antipain inhibits papain trypsin and plasmin. 

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