Elastase natural protein inhibitors

Proteolytic enzymes (proteases) are involved in a wide variety of physiological processes including digestion, fertilization, coagulation, and the immune response. Outside of their normal environment, proteases can be extremely destructive and natural human plasma inhibitors inhibit most proteases that escape. Imbalance in protease-protease inhibitor systems can lead to a number of diseases of which pulmonary emphysema is one well-characterized example. This disease results when the protease elastase attacks elas-tin, the major elastic protein in the lung. Considerable effort has been devoted to the synthesis of inhibitors of proteolytic enzymes such as elastase for possible therapeutic use. In the future, specific and selective synthetic protease inhibitors should be useful for treating specific diseases that range from the common cold to chronic disorders such as emphysema. 

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],... 

Even though serine proteinases share a common mechanism of peptide bond cleavage, they differ dramatically in their primary substrate specificity, exhibiting a preference for a certain type of amino acid residue. Hydrolysis studies using natural and synthetic substrates have demonstrated that NE preferentially cleaves peptide bonds after small aliphatic amino acid residues such as valine and alanine [21]. Elastase has been shown to have a pH optimum between 8.0 and 9.0 with most protein substrates and is strongly inhibited by the plasma inhibitor ai-PI. 

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