Cephalosporin antibiotics can be modified to inhibit human leukocyte elastase

Abstract

Several laboratories, including our own have reported the synthesis and activity of certain low relative molecular mass inhibitors of mammalian serine proteases, especially human leukocyte elastase (HLE, EC 3.4.21.37), an enzyme whose degradative activity on lung elastin has been implicated as a major causative factor in the induction of pulmonary emphysema, and which is present in the azurophil granules of human polymorphonuclear leukocytes (PMN). Normally, these granules fuse with phagosomes containing engulfed foreign material (such as bacteria), and HLE, in combination with other lysosomal enzymes, catabolizes the particles. Under certain pathological conditions, however, PMN become attached to host protein (elastin fibres, basement membrane, connective tissue, immune complexes), and in response to this adherence, the granules may fuse with the PMN outer membrane and release their contents, including HLE, directly onto the tissue. Besides emphysema, HLE may also contribute to the pathogenesis of disease states such as adult respiratory distress syndrome, and its potential involvement in rheumatoid arthritis makes HLE inhibitors of considerable interest. It is known that cephalosporin antibiotics (for example, cephalothin (compound I, Table 2)) are acylating inhibitors of bacterial serine proteases which help synthesize the cell wall by performing a transpeptidation reaction on a peptidyl substrate bearing a D-Ala-D-Ala terminus. We now report that neutral cephalosporins (that is, compounds not bearing a free carboxyl at position C-4) can be modified to become potent time-dependent inhibitors of HLE.

Targeting neutrophil elastase in cystic fibrosis

“…Although the irreversible inhibitors such as chloromethyl ketone have been shown to function effectively in vivo in hamsters to reduce many of the effects of intratracheally administered NE, the toxicity of chloromethyl ketones prevents clinical use. β-lactam-based compounds have been identified as specific potent inhibitors of NE [105]. The fact that these molecules clear rapidly from circulation suggests that they may be limited to aerosol therapy.…”

“…These include irreversible inhibitors such as the peptide chloromethyl ketones [101] and reversible inhibitors such as peptide boronic acids [102], peptide aldehydes [103], substituted tripeptide ketones [104], or β-lactams that have been modified to inhibit NE [105]. One of the problems with the low-molecular-weight reversible inhibitors is that they can release NE, allowing it to destroy tissue.…”

Functionalized N‐aryl azetidinones as novel mechanism‐based inhibitors of neutrophil elastase

“…hibitors of mammalian serine proteases such as ce-chymotrypsin. Recently, series of neutral derivatives of cephalosporins [8,91 and monocyclic d-lactams [10] Abbreviations: HLE, human leukocyte elastase (EC 3.4.21,37); PPE porcine pancreatic elastase (EC 3,4.21.36); Suc-AlapNA, succinyl. alanyl-alanyl-alanine p-nitroanilide; MeO-Suc-Alaz-Pro-Val.NA, methoxysuccinyl-alanyl.alanyl.prolyl.valyl p-nitroanilide; Ac-Tyr-NA, N-acetyl-L-tyrosine p-nitroanilide; Bz-Arg-NA, benzoyl.arginyl p-nitroanilide; S-2251, D-valyl-L-leucyl-L.lysine p-nitroanilide; S-2238, D-pl~enylalanine-L-pipecolyl-L.arginine p-nitroanilide,, PNA, p-nitropheayl acetate; NPGB, p-nitrophenyl p-guanidino.…”

Diverse Activities for Proteinases in the Pathogenesis of Chronic Obstructive Pulmonary Disease

“…A number of synthetic low molecular www.intechopen.com Chronic Obstructive Pulmonary Disease -Current Concepts and Practice 58 weight inhibitors have been developed and are potential therapeutic agents for COPD. These include irreversible inhibitors such as the peptide chloromethyl ketones (141) and reversible inhibitors such as peptide boronic acids, peptide aldehydes (142), substituted tripeptide ketones (143), or -lactams (144). One of the problems with the low-molecularweight reversible inhibitors is that they can release NE, allowing it to destroy tissue.…”