King's College London

Research portal

ADAM PROTEASE INHIBITION

Research output: Patent

Garrit Peter Koller (Inventor), Jörg W. Bartsch (Inventor)

Original languageEnglish
Patent number 20100291063
IPCActing on Peptide Bonds
Publication statusPublished - 8 Nov 2010

King's Authors

Abstract

ADAMs (a disintegrin and metalloprotease) or MDCs (metalloprotease disintegrin cysteine-rich proteins) form a family of type I transmembrane proteins. Owing to their multidomain structure consisting of pro-, metalloprotease, disintegrin-like, cystein-rich, EGF-like, transmembrane and cytoplasmic domains, ADAMs are capable of four physiological functions: cell adhesion, cell fusion, cell signalling and proteolysis.

ADAMs are implicated in physiological processes such as fertilisation, myogenesis and neurogenesis, and are also involved in a number of pathological processes by releasing cytokines and their receptors under inflammatory conditions (see for example Moss and Bartsch, 2004). To date, 40 members are known in different species (table of ADAMs on http://www.people.virginia.edu/;jw7g/). Approximately half of these ADAMs contain the catalytic consensus sequence HEXXHHXXGXXHD (SEQ ID NO:1) in their metalloprotease domains and are therefore predicted to be catalytically active. Proteolysis of membrane-anchored precursor proteins is a key event in signalling cascades (Blobel, 2005) and this process has been termed ectodomain shedding (Peschon et al., 1998). A number of ADAM substrates have been defined either by their physiological role or by their cellular localisation (Seals and Courtneidge, 2003; Moss and Bartsch, 2004; Blobel, 2005). So far, no consensus sequence on the substrate side has been reported, making prediction of potential cleavage sites difficult. Rather, ADAMs recognise a structural footprint on the extracellular part of the membrane protein, and it is assumed that cleavage occurs in the juxtamembraneous regions of these membrane proteins.

One particular area of research interest is the ADAM family member ADAM8, originally identified as MS2 or CD156 on mouse macrophages (Yoshida et al., 1990). ADAM8 is expressed in several tissues, such as thymus, cartilage, bone, brain and spinal cord, during embryonic development. As embryonic development of ADAM8-deficient mice appears normal, ADAM8 does not seem to be essential for developmental processes (Kelly et al., 2005). Rather, it is more likely that ADAM8 has a specific function in cytokine response which is reflected by its distinct expression in immune cells like B-cells, leukocytes, neutrophils, macrophages, and dendritic cells. In response to inflammatory stimuli such as lipopolysaccharide (LPS) and tumour necrosis factor a (TNF-α), ADAM8 expression is upregulated in most immune cells. In addition, ADAM8 is upregulated in the central nervous system (CNS) under inflammatory conditions in activated glia cells—astrocytes and microglia—indicating its involvement in neuron-glia signalling, in particular in neuroinflammatory disorders (Schlomann et al., 2000). Similarly to glial cells, ADAM8 is expressed in neurons at low levels, and expression is induced by TNF-α, suggesting that under inflammatory conditions in the CNS, neuronal ADAM8 activity is significantly increased (Schlomann et al., 2000).

In the lung, ADAM8 is upregulated under experimental induction of allergic asthma by inflammatory cytokines (King et al., 2004), suggesting that ADAM8 plays a role in the pathogenesis of allergic asthma. The induction of experimental asthma in ADAM8 deficient mice almost suppresses the asthmatic phenotype, arguing for an essential role of ADAM8 in the pathogenesis of allergic asthma.

All these findings underline the importance of ADAM8 in inflammatory processes and the necessity to inhibit ADAM8 activity under those pathological conditions where ADAM8 activity has detrimental effects.

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454