dc.contributor.author | Lalatsa, Aikaterini | |
dc.contributor.author | Sun, Yujiao | |
dc.contributor.author | Gamboa Landa, José Ignacio | |
dc.contributor.author | Knafo Farhi, Dina Shira | |
dc.date.accessioned | 2021-03-04T09:29:52Z | |
dc.date.available | 2021-03-04T09:29:52Z | |
dc.date.issued | 2020-08-04 | |
dc.identifier.citation | Pharmaceutical Research 37(10) : (2020) // Article ID 183 | es_ES |
dc.identifier.issn | 0724-8741 | |
dc.identifier.issn | 1573-904X | |
dc.identifier.uri | http://hdl.handle.net/10810/50464 | |
dc.description.abstract | PurposeAmyloid beta (A beta) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to A beta drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer's disease. Hence, the PTEN:PDZ interaction appears to be crucial for A beta -induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability.MethodsLipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken.ResultsThe mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp(0-4h): 6.281.85x10(-6) cm s(-1)).ConclusionThis increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery. | es_ES |
dc.description.sponsorship | The authors declare that this study received funding from MemoryPlus Ltd. The funder was not involved in the study design, collection, analysis, and interpretation of data. One of the authors of this article (SK) owns the controlling interest in MemoryPlus Ltd., and has filed an application for a U.S. Patent with respect to the compounds, compositions and methods mentioned in this article. SK was involved in the writing of this article and in the decision to submit it for publication. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Springer | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | Alzheimer's disease | es_ES |
dc.subject | blood-brain barrier | es_ES |
dc.subject | hCMEC | es_ES |
dc.subject | D3 human cerebral endothelial cells | es_ES |
dc.subject | PTEN-PDZ lipopeptides | es_ES |
dc.subject | stability | es_ES |
dc.subject | peptide | es_ES |
dc.subject | delivery | es_ES |
dc.subject | permeability | es_ES |
dc.subject | enzymes | es_ES |
dc.subject | growth | es_ES |
dc.subject | mouse | es_ES |
dc.title | Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer's Disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://link.springer.com/article/10.1007%2Fs11095-020-02915-8 | es_ES |
dc.identifier.doi | 10.1007/s11095-020-02915-8 | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoes | Química orgánica I | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |
dc.departamentoeu | Kimika organikoa I | es_ES |