Peptide-Based Inhibitors of ADAM and ADAMTS Metalloproteinases

Pluda, Stefano; Mazzocato, Ylenia; Angelini, Alessandro

doi:10.3389/fmolb.2021.703715

Cited by 16 publications

(16 citation statements)

References 71 publications

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“…A disintegrin and metalloproteases (ADAMS) comprise a Zn 2+ -dependent superfamily of secreted and membrane-bound sheddases, acting as “molecular scissors” as they proteolytically cleave the extracellular domain (ectodomain) of cell surface proteins, a process referred to as ectodomain shedding [ 29 , 38 , 39 ]. Ectodomain shedding controls the availability of the soluble active form of functional proteins such as growth factors, cytokines, cytokine receptors, adhesion proteins, and signaling molecules ([ 40 ]; for review: see [ 41 , 42 ]).…”

Section: Discussionmentioning

confidence: 99%

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ADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis

Meenen

Doege

Alefeld

et al. 2022

IJMS

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A disintegrin and metalloproteinase (ADAM) family proteins, acting as sheddases, are important factors in a number of pathologies, including cancer, and have been suggested as promising therapeutic targets. The study presented focuses on the involvement of ADAM10 and ADAM17 in retinoblastoma (RB), the most common malignant intraocular childhood tumor. A significant correlation between ADAM17 expression levels and RB laterality and RB staging was observed. Levels of ADAM10 or ADAM17 regulating miRNAs miR-145, -152, and -365 were significantly downregulated in RB cell lines, and reduced miR levels with simultaneously upregulated ADAM10 and ADAM17 expression were found in RB patients. The involvement of both ADAMs analyzed in ectodomain shedding of the neuronal cell adhesion molecule L1 (L1CAM), shown to induce pro-tumorigenic effects in RB, was confirmed. Lentiviral ADAM10 and ADAM17 single or ADAM10/17 double knockdown (KD) induced caspase-dependent apoptosis and reduced cell viability, proliferation, growth, and colony formation capacity of RB cells. Moreover, differential phosphorylation of the serine/threonine kinase AKT was observed following ADAM17 KD in RB cells. Chicken chorioallantoic membrane (CAM) assays revealed that ADAM17 and ADAM10/17 depletion decreases the tumorigenic and migration potential of RB cells in vivo. Thus, ADAMs are potential novel targets for future therapeutic RB approaches.

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Section: Discussionmentioning

confidence: 99%

“…In this context, ADAMs already represent important drug targets for the treatment of different human diseases. Different molecules, e.g., monoclonal antibodies, have been developed to inhibit ADAM proteins [ 29 ], rendering ADAM10 and ADAM17 potentially interesting targets in RB tumor therapy.…”

Section: Introductionmentioning

confidence: 99%

ADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis

Meenen

Doege

Alefeld

et al. 2022

IJMS

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“…Despite musculoskeletal syndrome as a side effect of early broadspectrum MMP inhibitors, several more selective MMP inhibitors, particularly those that inhibit MMP-2 or -9, have shown clinical benefit (108). These latter MMP inhibitors are protein-based, including antibodies and tissue inhibitors of MMPs (TIMPs), several of which are currently undergoing clinical trials (109), including an anti-MMP-9 antibody (110). Small peptide inhibitors of ADAM-17, which cleaves syndecan-1 and 4, have also been identified as potential therapeutics (109).…”

Section: Protease Inhibitorsmentioning

confidence: 99%

“…These latter MMP inhibitors are protein-based, including antibodies and tissue inhibitors of MMPs (TIMPs), several of which are currently undergoing clinical trials (109), including an anti-MMP-9 antibody (110). Small peptide inhibitors of ADAM-17, which cleaves syndecan-1 and 4, have also been identified as potential therapeutics (109).…”

Section: Protease Inhibitorsmentioning

confidence: 99%

Endothelial Glycocalyx Degradation in Critical Illness and Injury

2022

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The endothelial glycocalyx is a gel-like layer on the luminal side of blood vessels that is composed of glycosaminoglycans and the proteins that tether them to the plasma membrane. Interest in its properties and function has grown, particularly in the last decade, as its importance to endothelial barrier function has come to light. Endothelial glycocalyx studies have revealed that many critical illnesses result in its degradation or removal, contributing to endothelial dysfunction and barrier break-down. Loss of the endothelial glycocalyx facilitates the direct access of immune cells and deleterious agents (e.g., proteases and reactive oxygen species) to the endothelium, that can then further endothelial cell injury and dysfunction leading to complications such as edema, and thrombosis. Here, we briefly describe the endothelial glycocalyx and the primary components thought to be directly responsible for its degradation. We review recent literature relevant to glycocalyx damage in several critical illnesses (sepsis, COVID-19, trauma and diabetes) that share inflammation as a common denominator with actions by several common agents (hyaluronidases, proteases, reactive oxygen species, etc.). Finally, we briefly cover strategies and therapies that show promise in protecting or helping to rebuild the endothelial glycocalyx such as steroids, protease inhibitors, anticoagulants and resuscitation strategies.

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“…However, like small molecules, peptides can be synthesized chemically and are thus cheaper to produce than recombinant proteins. Other advantages include low toxicity and reduced antigenicity . Therefore, peptide-based inhibitors are potentially endowed with the advantages of the two different classes of molecules.…”

Section: Exosite Inhibitorsmentioning

confidence: 99%

Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition

et al. 2022

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Osteoarthritis (OA) is the most common degenerative joint disease. In 1999, two members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family of metalloproteinases, ADAMTS4 and ADAMTS5, or aggrecanases, were identified as the enzymes responsible for aggrecan degradation in cartilage. The first aggrecanase inhibitors targeted the active site by chelation of the catalytic zinc ion. Due to the generally disappointing performance of zinc-chelating inhibitors in preclinical and clinical studies, inhibition strategies tried to move away from the active-site zinc in order to improve selectivity. Exosite inhibitors bind to proteoglycan-binding residues present on the aggrecanase ancillary domains (called exosites). While exosite inhibitors are generally more selective than zinc-chelating inhibitors, they are still far from fulfilling their potential, partly due to a lack of structural and functional data on aggrecanase exosites. Filling this gap will inform the design of novel potent, selective aggrecanase inhibitors.

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Peptide-Based Inhibitors of ADAM and ADAMTS Metalloproteinases

Cited by 16 publications

References 71 publications

ADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis

ADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis

Endothelial Glycocalyx Degradation in Critical Illness and Injury

Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition

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