Neprilysin expression and functions in development, ageing and disease

Наливаева, Н. Н.; Журавин, И. А.; Turner, Amy

doi:10.1016/j.mad.2020.111363

Cited by 113 publications

(115 citation statements)

References 188 publications

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“…In conclusion, based on its numerous biological functions [ 107 ], neprilysin decreased presence may have serious effects in concentrations of extracellular bioactive-molecules, in membrane/cytoskeleton micro-domains organization, and related signal transduction. These may indeed result in defective differentiation and physiology of different cell types and organs, such as bone, brain, heart, lung, and kidney [ 107 ].…”

Section: Resultsmentioning

confidence: 99%

Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

Bini

Schvartz²,

Carnemolla

et al. 2021

IJMS

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Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non–collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.

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Section: Resultsmentioning

confidence: 99%

Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

Bini

Schvartz²,

Carnemolla

et al. 2021

IJMS

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“…The neprilysin-Amyloidβ (Aβ) was selected as the enzyme-substrate prototype as recent studies have indicate the potential role of developing recombinant neprilysin as a therapeutic candidate for treating Alzheimer's disease (AD). 2,6,8,9,16 Therapeutic development of neprilysin for use in treating AD will require establishing the optimal enzyme kinetics against AD specific Aβ peptides. 2,8,9 Although the association Aβ peptides in the progression of AD is well established, developing effective treatment will require specific and selective cleaving of a variety of Aβ peptides.…”

Section: Discussionmentioning

confidence: 99%

“…2,6,8,9,16 Therapeutic development of neprilysin for use in treating AD will require establishing the optimal enzyme kinetics against AD specific Aβ peptides. 2,8,9 Although the association Aβ peptides in the progression of AD is well established, developing effective treatment will require specific and selective cleaving of a variety of Aβ peptides. [14][15][16][17] Depending on the variation in the site of cleavage in the amyloid precursor protein a variety of Aβ peptides can be generated, which may impact the pathophysiology of AD differently.…”

Section: Discussionmentioning

confidence: 99%

Modelling the efficacy of Neprilysin from various species in degrading different Amyloid-β peptides: Potential application in therapeutics of Alzheimer’s disease

Kumar

2021

Preprint

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Recombinant neprilysin due to its degradation potential against Amyloid-beta (A-beta) peptides has been looked at as a potential therapeutic candidate for treating Alzheimers disease (AD). However the enzymatic activity of neprilysin against different Aβ peptides can variable which significantly limits the therapeutic optimization. Using the molecular interaction analysis and modelling it against the known enzyme-substrate kinetics, this study developed a novel approach to predicting biosimilar enzyme-substrate kinetics. The known enzyme-substrate kinetics of human recombinant neprilysin with A-beta1-40 peptide was used as the prototype to assess the affinity and efficacy of various inter and intra-species neprilysin- A-beta peptide enzyme kinetics based on the relative molecular interaction analysis. Significant inter and intra-species variations in neprilysin- A-beta peptide enzyme kinetics was observed which further validated the need for optimizing enzyme kinetics tailored to specific substrate degradation. The novel enzyme kinetics modelling approach described in this study can be helpful in the developing of recombinant enzymes/peptides for personalised therapeutic applications.

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“…Neprilysin is a widely expressed peptidase located on the cell surface and has very diverse substrate speci city (Esser and Zraika, 2019;Karoor et al, 2013;Nalivaeva et al, 2020). Due to its diverse substrate speci city it is involved in regulating variety of physiological (electrolyte balance, blood pressure regulation, analgesia) and pathological (T cell lymphoma, Alzheimer's, diabetes, diarrhoea) process.…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling of Neprilysin expression and its interactions with SARS-CoV-2 spike proteins to develop evidence base pharmacological approaches for therapeutic intervention

Kumar

2021

Preprint

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Neprilysin due to its peptidase activity is involved in several physiological and pathological processes. Recently our group has reported the association of neprilysin with angiotensin-converting enzyme 2 (ACE2) network proteins which facilitate the entry of SARS-COV2 virus. The potential role of neprilysin beyond its peptidase activity is not known. Using the established sequence analysis and molecular docking tools, this study evaluated the molecular profile of neprilysin interaction with SARS-COV2 virus proteins. Human neprilysin protein showed a significant sequence similarity with SARS-COV2 spike protein, which was further confirmed by observation of considerable interaction in the molecular docking. Human neprilysin protein was also found to additionally interact with SARS-COV2 proteins facilitating virus replication. The potential of neprilysin inhibitors (Sacubitril and Sacubitrilat) to interfere with neprilysin and SARS-COV2 proteins interactions was assessed. The neprilysin inhibitors showed binding efficacy within therapeutically feasible concentration range (1 to 150 uM). This study while reporting a novel role of neprilysin as potential receptor for SARS-COV2 virus, highlights the merit in assessing clinical efficacy of neprilysin inhibitors for the management of SARS-COV2 infection.

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Neprilysin expression and functions in development, ageing and disease

Cited by 113 publications

References 188 publications

Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

Modelling the efficacy of Neprilysin from various species in degrading different Amyloid-β peptides: Potential application in therapeutics of Alzheimer’s disease

Molecular profiling of Neprilysin expression and its interactions with SARS-CoV-2 spike proteins to develop evidence base pharmacological approaches for therapeutic intervention

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