Glutamic acid peptides inhibitors

Trypsin inhibitors in cucumber were first found in a study by Walker-Simmons et /. " after wounding of leaves and treatment with proteinase inhibitor-inducing factor (PIIF). The amino acid sequence of two inhibitors isolated from Cucurhita maxima (winter squash) were determined by Wilusz et at The peptides named ITD I and ITD 111 each comprised a 29-residue sequence with six cysteine residues. The only difference between the two peptides is in position 9, which is lysine in ITD I and glutamic acid in ITD III. The reactive site is located at the peptide bond between Arg5 and Ile6. Owing to their discovery and distribution in Cucurbitaceae the inhibitor family has been named squash inhibitors. Since the initial discoveries many other members of the squash family have been found. 

Some other peptides, e.g., dipeptidyl peptidase IV (8), endopeptidase 3.4.24.16 inhibitor (9), and a copolymer of tyrosine, glutamic acid, alanine, and lysine (10), have also demonstrated immunomodulatory activity. Thus analogues of these may some day play an important role in treatment of autoimmune and inflammatory diseases. It should also be noted that a vast number of naturally derived peptides also has demonstrated antimicrobial activity toward a wide range of pathogens (11), resulting in possible templates for further optimization studies clearly demonstrating the potential importance of peptides as pharmacological tools. 

The specificity of poliovirus protease may be inferred from end group analyses of processed virus capsid polypeptides. The enzyme cleaves peptide bonds whose carboxyl group is donated by leucine or glutamic acid residues. This permitted use of a synthetic protease inhibitor terminating in a leucyl chloromethyl... 

Phosphonates have been widely used as analogues of carboxylic acids. They have been particularly effective as analogues of tetrahedral transition states that occur in the course of enzyme-catalyzed reactions such as hydrolysis of the amide (peptide) bond. As such, they may be used as inhibitors of enzymes (e.g., 82, 83) or as haptens for producing antibodies that are catalytic (e.g., 84). A notable example is H203P— CH2—CH2—CH(—NH2)—COOH, which has effects that are likely to be due to its interference with glutamate as a neurotransmitter (85). 

In 1972 the team of Professor Zaehner at Tubingen described a Streptomyces strain producing a novel compound with antibiotic properties. The antibiotic tripeptide produced by Streptomyces viridochromogenes consists of two alanine residues and a novel amino acid that was named phosphinothricin [14] (Fig. 6.3.2). Owing to its structural analogy to glutamate Bayer et al. [14] tested and proved the hypothesis that phosphinothricin acts as an inhibitor of bacterial GS enzyme, whereas the tripeptide phosphinothricyl-alanyl.alanine did not inhibit the isolated GS enzyme. Nevertheless the tripeptide was 1.000-10.000-fold more active in its growth inhibitory effect on different bacteria. The discrepancy is explained by the observation that free phosphinothricin cannot be taken up efficiently by bacteria, whereas the tripeptide is taken up into the bacteria by peptide carriers and, subsequently, the tripeptide is cleaved. 

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