Intramembrane proteases as drug targets

Verhelst, Steven H. L.

doi:10.1111/febs.13979

Cited by 35 publications

(36 citation statements)

References 114 publications

(146 reference statements)

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“…Proteases are found in virtually every cell and tissue type, and conduct a remarkably broad range of biological functions. As such, proteases are of tremendous interest as both specific targets for drug discovery [2–4] as well as objects of fundamental mechanistic interest. In addition to substrate specificity, a critical aspect of the characterization of proteases is analysis of their kinetics.…”

Section: Introductionmentioning

confidence: 99%

Acquisition of accurate data from intramolecular quenched fluorescence protease assays

Arachea

Wiener

2017

Analytical Biochemistry

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The Intramolecular Quenched Fluorescence (IQF) protease assay utilizes peptide substrates containing donor-quencher pairs that flank the scissile bond. Following protease cleavage, the dequenched donor emission of the product is subsequently measured. Inspection of the IQF literature indicates that rigorous treatment of systematic errors in observed fluorescence arising from inner-filter absorbance (IF) and non-specific intermolecular quenching (NSQ) is incompletely performed. As substrate and product concentrations vary during the time-course of enzyme activity, iterative solution of the kinetic rate equations is, generally, required to obtain the proper time-dependent correction to the initial velocity fluorescence data. Here, we demonstrate that, if the IQF assay is performed under conditions where IF and NSQ are approximately constant during the measurement of initial velocity for a given initial substrate concentration, then a simple correction as a function of initial substrate concentration can be derived and utilized to obtain accurate initial velocity data for analysis.

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Section: Introductionmentioning

confidence: 99%

Acquisition of accurate data from intramolecular quenched fluorescence protease assays

Arachea

Wiener

2017

Analytical Biochemistry

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“…Secondly, the γ‐secretase presents the remarkable ability to cleave peptide bonds within the lipid bilayer of the membrane whereby a highly hydrophobic environment is not a priority in being conducive for hydrolysis. Nevertheless, an increasing number of such activities grouped under the term “Intramembrane‐cleaving proteases” (iCLips) has been described during the past years . These enzymes, including Signal Peptide Peptidase‐zinc metalloproteases (S2P), rhomboid serine proteases, and GxGD‐type aspartyl proteases, are concluding a two‐step regulated intramembrane proteolysis (RIP) process that is usually initiated by ectodomain shedding (α or β cleavages in the case of βAPP).…”

Section: Secretase Familiesmentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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“…Intramembrane proteases (IMPs), a fairly recently discovered class, are embedded in lipid bilayers and their catalytic site is formed by residues in different transmembrane helices [82]. The four IMP families are metallo-, serine, aspartate and glutamate proteases, and they are found in the Golgi apparatus, endosomes and lysosomes, the plasma membrane, endoplasmatic reticulum, and the inner mitochondrial membrane.…”

Section: Regulation Of Physiological Processesmentioning

confidence: 99%

“…Antibody therapy with Rituximab targets CD20 on the B cell surface, triggering cell death, and is used for B cell depletion to treat rheumatoid arthritis, idiopathic thrombocytopenic purpura, pemphigus vulgaris and myasthenia gravis. The recent discovery that the intramembrane signal peptide peptidase-like protease SPPL2A promotes B cell differentiation by cleavage of CD74 suggested that SPPL2A may be a suitable target for inhibition in the treatment of autoimmune diseases [82]. Major histocompatibility complex (MHC) class II-mediated priming of T and B lymphocytes occurs in systemic lupus erythematosus (SLE) and lupus nephritis.…”

Section: Proteases and Diseasementioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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Intramembrane proteases as drug targets

Cited by 35 publications

References 114 publications

Acquisition of accurate data from intramolecular quenched fluorescence protease assays

Acquisition of accurate data from intramolecular quenched fluorescence protease assays

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Proteases: Pivot Points in Functional Proteomics

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