Abstract
For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.
Highlights
The role of ADAM17 in inflammation became evident as soon as it was identified as the enzyme responsible for the release of soluble tumor necrosis factor α (TNF)
Given the crucial role of iRhoms in ADAM17 activity, these results suggest that iRhoms, to ADAM17, may take contacts with its substrates, which can be disrupted by negatively charged residues within their stalk region
ADAM17 is ubiquitously expressed in human, and it has been identified as the sheddase responsible for cleavage of over 80 substrates other than TNF
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. TNF was first cloned in 1984, and four years later, discovered to be a transmembrane protein that needs to be proteolytically released from the cell surface in order to elicit its pro-inflammatory potential [6,7]. Since targeting ADAM17 for drug development and fighting inflammatory diseases seemed to be the natural consequence of its discovery This process has been much harder than expected and never fully accomplished. The first drugs targeting the activity of ADAM17, despite the huge expectations, have never made it into the clinics, as the side effects that they caused were more severe than the benefits [10] These inhibitors blocked the activity of many other metalloproteinases that share with ADAM17 a conserved catalytic domain, deregulating a vast number of physiological processes.
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