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Published on: May 24, 2024
Considerations on inhibition approaches for proinflammatory functions of ADAM proteases
Daniela Dreymueller1, Andreas Ludwig1
1a Institute of Pharmacology and Toxicology , RWTH Aachen University , Aachen , Germany.
Abstract:
Proteases of the disintegrin and metalloproteinase (ADAM) family mediate the proteolytic shedding of various surface molecules including cytokine precursors, adhesion molecules, growth factors, and receptors. Within the vasculature ADAM10 and ADAM17 regulate endothelial permeability, transendothelial leukocyte migration, and the adhesion of leukocytes and platelets. In vivo studies show that both proteases are implicated in several inflammatory pathologies, for example, edema formation, leukocyte infiltration, and thrombosis. However, both proteases also contribute to developmental and regenerative processes. Thus, although ADAMs can be regarded as valuable drug targets in many aspects, the danger of severe side effects is clearly visible. To circumvent these side effects, traditional inhibition approaches have to be improved to target ADAMs at the right time in the right place. Moreover, the inhibitors need to be more selective for the target protease and if possible also for the substrate. Antibodies recognizing the active conformation of ADAMs or small molecules blocking exosites of ADAM proteases may represent inhibitors with the desired selectivities.
Insights
Disintegrin and metalloproteinase (ADAM) proteases are crucial in vascular inflammation but also development. Novel inhibitors targeting specific ADAM proteases and substrates are needed to minimize side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Vascular Biology
Background:
- Proteases of the disintegrin and metalloproteinase (ADAM) family are involved in shedding surface molecules.
- ADAM10 and ADAM17 play key roles in vascular functions, including endothelial permeability and leukocyte adhesion.
- These proteases are implicated in inflammatory diseases but also in development and regeneration.
Purpose of the Study:
- To discuss the dual role of ADAM proteases in vascular physiology and pathology.
- To highlight the challenges and potential strategies for developing targeted ADAM inhibitors.
- To explore novel approaches for selective inhibition of ADAM proteases.
Main Methods:
- Review of existing literature on ADAM proteases in vascular biology and inflammation.
- Analysis of in vivo studies demonstrating the roles of ADAM10 and ADAM17.
- Discussion of potential therapeutic strategies for selective inhibition.
Main Results:
- ADAM proteases regulate critical vascular processes and are implicated in inflammatory pathologies.
- ADAM proteases are essential for normal development and tissue regeneration.
- Non-selective inhibition of ADAM proteases carries a high risk of severe side effects.
Conclusions:
- Targeted inhibition strategies are necessary to mitigate side effects associated with ADAM protease inhibition.
- Developing inhibitors with increased selectivity for specific ADAM proteases and substrates is crucial.
- Antibodies targeting active ADAM conformations or small molecules blocking exosites show promise for selective inhibition.
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