Inhibitors, connective tissue

The /3-lactam structure can also react with active-serine hydrolases other than PBPs and /3-lactamases. It has been shown that appropriately substituted cephalosporins (e.g., 5.18) are potent mechanism-based inactivators of human leukocyte elastase (HLE, EC 3.4.21.37), a serine endopeptidase involved in the pathogenesis of pulmonary emphysema and other connective tissue diseases [57-60]. Subsequent work has demonstrated that substituted /3-lactams such as 5.19 or 5.20 are more stable HLE inhibitors and have improved potencies [61-63]. 

The proteolytic load a connective tissue endures during inflammation is a balance between the activity of the proteinases secreted by inflammatory cells and the local specific activity of functional plasma inhibitors. During inflammatory episodes, oxidative inactivation of specific inhibitors may move this delicate balance so that connective tissue macromolecule proteolysis is favoured (see Fig. 2). 

As with all complex biological systems we should not forget the close interplay between oxidative and proteolytic systems (see Fig. 2). For example, it has been shown that at a localised inflammatory site, oxidative inactivation of protease inhibitors may lead to a proteolytic cascade resulting in down-stream MMP activation through the localised action of serine proteinases activating previously latent MMPs (see Fig. 2). Equally, the generation of active MMPs (post-oxidant exposure) may be involved in the site-specific catalytic inactivation of serine-protease inhibitors [59] at an inflammatory site with the consequent generation of an elevated serine protease load and connective tissue proteolysis (see Fig. 2). 

Crofford LJ, Oates JC, McCune WJ, Gupta S, Kaplan MJ, Catella-Lawson F, Morrow JD, McDonagh KT, Schmaier AH. Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases. Arthritis Rheum 2000 43(8) 1891-6. 

Human leucocyte elastase (HE) is released in response to inflammatory stimuli and is responsible for degradation of connective tissues and is implicated in respiratory distress syndrome, rheumatoid arthritis, chronic bronchitis, and pulmonary emphysema. Many inhibitors of HE have been described [5], usually of the electrophilic carbonyl type, and often the key Val-Pro-Val motif has been exploited for potent inhibitory activity (3 - 5, Fig. 3). Recently, sivelestat (6, HE IC50 = 44 nM), a member of an enzyme-acylating series, has been approved in Japan for the treatment of acute lung injury [6]. 

Cawston, T.E. (1996) Metalloproteinase inhibitors and the prevention of connective tissue breakdown. Pharmacol. Then. 70.163-182. 

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