Editorial [Hot Topic: Tumour Necrosis Factor Alpha Converting Enzyme (,Guest Editor: David Fairlie)]

To the medicinal chemist uninitiated in the field, inflammation can be an intimidating research area to tackle. There is a bewildering array of prospective targets for antiinflammatory drugs, with countless enzyme inhibitors, receptor antagonists, and other experimental antiinflammatory agents already known. Despite many decades of research, the biology that underpins inflammation, the immune response to infection and injury, and the mechanistic basis for therapies, is still in need of considerable unravelling. Fortunately, the genomic/proteomic revolution that has been taking place is providing new tools and an unprecedented volume of new information that promises to dramatically improve our understanding of inflammatory networks, and how best to intervene in them for maximum therapeutic gain. In this issue, Hume et al. present a short commentary on inflammation and inflammatory targets of relevance to other articles that follow. They describe some factors that limit either the effectiveness of inflammatory targets or the rate of discovery of antiinflammatory drugs, and comment briefly on future prospects for targeting proteins that mediate inflammatory responses. Whitehouse completes the introduction by overviewing the historical development of antiinflammatory therapies, focussing on some of the problems encountered in drug development during the past century and some important lessons that were learned along the way. Brown describes antibody treatments for inflammatory arthritis (e.g. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis), including some of their limitations as well as opportunities for developing new antibody based anti-inflammatory therapies. Kanwar also overviews antibody therapies, but for the treatment of multiple sclerosis, including properties of antibodies in animal models of experimental autoimmune encephalomyelitis (EAE). Numerous proteolytic enzymes are implicated in the pathogenesis of chronic inflammatory diseases. Abbenante and Le describe the current status of development of small nonpeptidic inhibitors of two such enzymes, the metalloprotease TACE (Tumour necrosis factor Alpha Converting Enzyme) and the cysteine protease Caspase-1 (formerly ICE, Interleukin Converting Enzyme). Such enzymes are responsible for producing the crucial proinflammatory mediators TNFα and IL1β, and selective inhibitors of such enzymes are expected to be effective antinflammatory drugs that should also be much cheaper and more accessible to the public than currently used antibody based therapies. Lee and Dominguez describe some clinical results for inhibitors of the serine/threonine kinase known as mitogen-activated protein kinase p38 (MAP kinase p38) and especially focus on inhibitor interactions with the best studied isoform, p38α protein. Kostadinova et al. overview peroxisome proliferator-activated receptors (PPARs) and their inhibitors in inflammation and disease. Reid surveys structures of inhibitors of secreted phospholipase A2 (group IIa) and discusses their potential roles as antiinflammatory drugs. Blakeney et al. survey some 30 GPCRs implicated in inflammation and describe structures and properties of some 60 agonists/antagonists with antiinflammatory activity. This issue represents only a tiny fraction of the already known number of inflammatory drug targets but offers a reasonable platform for benchmarking future developments in antiinflammatory drugs both for these targets and others.