ArticlePloS one2014
Engineering neprilysin activity and specificity to create a novel therapeutic for Alzheimer's disease.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 72 citations in OpenAlex.
- Modest Contribution of Bradykinin to Blood Pressure Reduction by Sacubitril/Valsartan in Chronic Heart Failure.Circulation. Heart failure · 2026Trial
- The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.The Biochemical journal · 2026Review
- Breaking barriers: Neprilysin inhibition in chronic cardiorenal syndrome.World journal of cardiology · 2025Review
- Machine-guided dual-objective protein engineering for deimmunization and therapeutic functions.Cell systems · 2025Article
- Pilot-Scale Production of Sericin-Derived Oligopeptides (SDOs) from Yellow Silk Cocoons: Peptide Characterization and Specifications.Foods (Basel, Switzerland) · 2025Article
- Effect of Mutation Type on Ectopic Ossification Among Adult Patients With X-Linked Hypophosphatemia.Journal of the Endocrine Society · 2024Article
- Blood-brain barrier penetrating neprilysin degrades monomeric amyloid-beta in a mouse model of Alzheimer's disease.Alzheimer's research & therapy · 2022Article
- Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases.Biology · 2022Review
- The past, present, and future of enzyme-based therapies.Drug discovery today · 2022Review
- Amyloid Beta Dynamics in Biological Fluids-Therapeutic Impact.Journal of clinical medicine · 2021Review
- Addressing the Selectivity of Enzyme Biosensors: Solutions and Perspectives.Sensors (Basel, Switzerland) · 2021Review
- Neprilysin inhibition, endorphin dynamics, and early symptomatic improvement in heart failure: a pilot study.ESC heart failure · 2020Observational
- Extracellular Vesicles as a Neprilysin Delivery System Memory Improvement in Alzheimer's Disease.Iranian journal of pharmaceutical research : IJPR · 2020Article
- Structures of soluble rabbit neprilysin complexed with phosphoramidon or thiorphan.Acta crystallographica. Section F, Structural biology communications · 2019Article
- Membrane metallo-endopeptidase (Neprilysin) regulates inflammatory response and insulin signaling in white preadipocytes.Molecular metabolism · 2019Article
- X-Ray Crystallography in Structure-Function Characterization of Therapeutic Enzymes.Advances in experimental medicine and biology · 2019Review
- Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism.Molecular neurodegeneration · 2018Article
- Impact of prolonged utilization of neprilysin inhibition on the cognitive function of heart failure patients.Therapeutic advances in cardiovascular disease · 2018Article
- Is Entresto good for the brain?World journal of cardiology · 2017Review
- Reprogramming Caspase-7 Specificity by Regio-Specific Mutations and Selection Provides Alternate Solutions for Substrate Recognition.ACS chemical biology · 2016Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neprilysin is a transmembrane zinc metallopeptidase that degrades a wide range of peptide substrates. It has received attention as a potential therapy for Alzheimer's disease due to its ability to degrade the peptide amyloid beta. However, its broad range of peptide substrates has the potential to limit its therapeutic use due to degradation of additional peptides substrates that tightly regulate many physiological processes. We sought to generate a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta as a potential therapeutic for Alzheimer's disease. Extensive amino acid substitutions were performed at positions surrounding the active site and inner surface of the enzyme and variants screened for activity on amyloid beta 1-40, 1-42 and a variety of other physiologically relevant peptides. We identified several mutations that modulated and improved both enzyme selectivity and intrinsic activity. Neprilysin variant G399V/G714K displayed an approximately 20-fold improved activity on amyloid beta 1-40 and up to a 3,200-fold reduction in activity on other peptides. Along with the altered peptide substrate specificity, the mutant enzyme produced a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme. Crystallisation of the mutant enzyme revealed that the amino acid substitutions result in alteration of the shape and size of the pocket containing the active site compared to the wild-type enzyme. The mutant enzyme offers the potential for the more efficient degradation of amyloid beta in vivo as a therapeutic for the treatment of Alzheimer's disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.