Abstract
The reaction of a series of azapeptides with porcine pancreatic (PP) elastase and human leukocyte (HL) elastase has been studied and a series of new inhibitors and active site titrants were found for both PP elastase and HL elastase. Azapeptide p-nitrophenyl esters acylate both HL and PP elastase to form stable acylenzymes, which can be used for crystallographic studies. We have investigated the effect of a P1, P2, or P3 aza-amino acid residue on the reactivity of azapeptides with elastase. We have also studied the effect of changing the nature of the P1' leaving group and other portions of azapeptide structure. N-Acetyl-L-alanyl-L-alanyl-alpha-azaalanine p-nitrophenyl ester, N-acetyl-L-alanyl-L-alanyl-alpha-azanorleucine p-nitrophenyl ester, and N-acetyl-L-alanyl-L-alanyl-alpha-azanorvaline p-nitrophenyl ester are suitable titrants for either PP or HL elastase.
Highlights
The reaction of a series of azapeptides with porcine pancreatic (PP) elastase and human leukocyte (HL) elastase has been studied and aseries of new inhibitors and active site titrants wefroeund for both PP elastase and HL elastase
This enzyme is found in the granule fraction of human polymorphonuclear leukocytes and is a typical serine protease belonging to thesame family as themore widely studied PP elastase
Proteolysis of lung elastin by HL elastase and other proteases released from the granule fraction of human polymorphonuclear leukocytes is generally thought to cause the tissue destruction observed in pulmonary emphysema
Summary
Since elastase inhibitors have considerable potential for use in therapy, synthetic inhibitors have been developed by ourselves and a number of other research groups (see Powers (1983) for a recent review) Some of these inhibitors have been shown to be effective in animal models of emphysema. In thepreceding paper (Gupton et ai., 1984), we have shown that azapeptides’ are effective inhibitors of serine proteases, can be used as active site titrants, andcan be used to generate stable acyl derivatives for crystallographic investigations. We have investigated the effect of changes in the nature of the PI‘leaving group and in other portionsof the azapeptide structure These investigations extend our knowledge of the active site of elastase and the types of molecules which will bind and react with it
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