Peptide arginals

A group of peptide derivatives such as peptide arginals and boronic acid peptide derivatives belong to another class of reversible thrombin inhibitors. One such inhibitor is PPACK (D-Phe-Pro-Arg chloromethyl ketone), which functions as a powerful irreversible thrombin inhibitor by alkylating the histidine residue at the catalytic site of thrombin (58). It, however, is unstable in neutral solution, as it undergoes cyclization and inactivation. However, the D-methyl derivative of D-Phe-Pro-Arg-H (D-Mephe-Pro-Arg-H) called efegatran, with a molecular mass of 515 Da, is a stable selective reversible inhibitor of thrombin with a K. of approximately 100 nM. The basic amino terminus in this compound is responsible for promoting the specificity toward thrombin (63). 

Peptides and their derivatives napeagatran) Peptide arginals (efegatran) Phase D clinical development... 

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. 

In aqueous solutions, peptide aldehydes exist as an equilibrium state between the aldehyde (A) and hydrated forms (B). In the example presented here (Figure 14), leupeptin, the C-terminal arginal, can also cyclize to form the aminol (C). The same equilibrium states are seen in the reverse-phase HPLC chromatogram (three broad peaks). The electrospray mass spectrum shows only the [M + H]+ (A and C) and [M -I- H + 18 (HzO)] (B) peaks. 

The specificity of the trypsin is very high. Trypsin attacks peptide bonds formed by the carboxyl group of a basic amino acid argine and lysine with the amino group of another amino acid. Consequently, when the number of basic amino acids in a substrate is known, the exact number of polypeptides that will appear in trypsin can be predicted. 

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