Proteinaceous elastase inhibitors

There are many high-molecular-weight, polypeptide, elastase inhibitors which have been isolated from animal or plant sources. Most of these, the non-human proteins, would probably induce an immunogenic response and are not suitable for clinical development. However, a subset of these inhibitors, predominantly human in origin, is being explored as a source for clinically-useful elastase inhibitors. Each of the human compounds is found in a specific location, which probably is its primary site for inhibitory action. The physical properties of many of these natural inhibitors have been reported (see Table 2.i)[45-51]. Due to their size and other physical properties, only intravenous or topical formulations of the proteinaceous inhibitors have been considered for clinical use. The pharmacological studies have included natural inhibitors, recombinant variants (i.e. peptides with identical sequences to the natural inhibitors but not necessarily the same glycosylation) and recombinant mutants (peptides with unnatural sequences) [52],... 

Theoretically, all of the proteinaceous inhibitors act by presenting a loop portion of their chains as an idealized, that is, pre-organized for optimal interactions, substrate for elastase. Conformational analysis of the inhibitor residues P P3 and P1-P3 for a series of proteinaceous, serine protease inhibitors showed that there is little difference between their free and/or complexed states [63]. In aj-PI, the loop contains as its elastase reactive center (see Table 2.2) a Met-Ser linkage. The importance of the P,-substituent in a PI for its enzyme specificity characteristics is exempli-... 

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