Cargando…

Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display

Alzheimer's disease and other Tauopathies are associated with neurofibrillary tangles composed of Tau protein, as well as toxic Tau oligomers. Therefore, inhibitors of pathological Tau aggregation are potentially useful candidates for future therapies targeting Tauopathies. Two hexapeptides wit...

Descripción completa

Detalles Bibliográficos
Autores principales: Malhis, Marwa, Kaniyappan, Senthilvelrajan, Aillaud, Isabelle, Chandupatla, Ram Reddy, Ramirez, Lisa Marie, Zweckstetter, Markus, Horn, Anselm H. C., Mandelkow, Eckhard, Sticht, Heinrich, Funke, Susanne Aileen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596876/
https://www.ncbi.nlm.nih.gov/pubmed/34375027
http://dx.doi.org/10.1002/cbic.202100287
_version_ 1784600487010500608
author Malhis, Marwa
Kaniyappan, Senthilvelrajan
Aillaud, Isabelle
Chandupatla, Ram Reddy
Ramirez, Lisa Marie
Zweckstetter, Markus
Horn, Anselm H. C.
Mandelkow, Eckhard
Sticht, Heinrich
Funke, Susanne Aileen
author_facet Malhis, Marwa
Kaniyappan, Senthilvelrajan
Aillaud, Isabelle
Chandupatla, Ram Reddy
Ramirez, Lisa Marie
Zweckstetter, Markus
Horn, Anselm H. C.
Mandelkow, Eckhard
Sticht, Heinrich
Funke, Susanne Aileen
author_sort Malhis, Marwa
collection PubMed
description Alzheimer's disease and other Tauopathies are associated with neurofibrillary tangles composed of Tau protein, as well as toxic Tau oligomers. Therefore, inhibitors of pathological Tau aggregation are potentially useful candidates for future therapies targeting Tauopathies. Two hexapeptides within Tau, designated PHF6* (275‐VQIINK‐280) and PHF6 (306‐VQIVYK‐311), are known to promote Tau aggregation. Recently, the PHF6* segment has been described as the more potent driver of Tau aggregation. We therefore employed mirror‐image phage display with a large peptide library to identify PHF6* fibril binding peptides consisting of D‐enantiomeric amino acids. The suitability of D‐enantiomeric peptides for in vivo applications, which are protease stable and less immunogenic than L‐peptides, has already been demonstrated. The identified D‐enantiomeric peptide MMD3 and its retro‐inverso form, designated MMD3rev, inhibited in vitro fibrillization of the PHF6* peptide, the repeat domain of Tau as well as full‐length Tau. Dynamic light scattering, pelleting assays and atomic force microscopy demonstrated that MMD3 prevents the formation of tau β‐sheet‐rich fibrils by diverting Tau into large amorphous aggregates. NMR data suggest that the D‐enantiomeric peptides bound to Tau monomers with rather low affinity, but ELISA (enzyme‐linked immunosorbent assay) data demonstrated binding to PHF6* and full length Tau fibrils. In addition, molecular insight into the binding mode of MMD3 to PHF6* fibrils were gained by in silico modelling. The identified PHF6*‐targeting peptides were able to penetrate cells. The study establishes PHF6* fibril binding peptides consisting of D‐enantiomeric amino acids as potential molecules for therapeutic and diagnostic applications in AD research.
format Online
Article
Text
id pubmed-8596876
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-85968762021-11-22 Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display Malhis, Marwa Kaniyappan, Senthilvelrajan Aillaud, Isabelle Chandupatla, Ram Reddy Ramirez, Lisa Marie Zweckstetter, Markus Horn, Anselm H. C. Mandelkow, Eckhard Sticht, Heinrich Funke, Susanne Aileen Chembiochem Full Papers Alzheimer's disease and other Tauopathies are associated with neurofibrillary tangles composed of Tau protein, as well as toxic Tau oligomers. Therefore, inhibitors of pathological Tau aggregation are potentially useful candidates for future therapies targeting Tauopathies. Two hexapeptides within Tau, designated PHF6* (275‐VQIINK‐280) and PHF6 (306‐VQIVYK‐311), are known to promote Tau aggregation. Recently, the PHF6* segment has been described as the more potent driver of Tau aggregation. We therefore employed mirror‐image phage display with a large peptide library to identify PHF6* fibril binding peptides consisting of D‐enantiomeric amino acids. The suitability of D‐enantiomeric peptides for in vivo applications, which are protease stable and less immunogenic than L‐peptides, has already been demonstrated. The identified D‐enantiomeric peptide MMD3 and its retro‐inverso form, designated MMD3rev, inhibited in vitro fibrillization of the PHF6* peptide, the repeat domain of Tau as well as full‐length Tau. Dynamic light scattering, pelleting assays and atomic force microscopy demonstrated that MMD3 prevents the formation of tau β‐sheet‐rich fibrils by diverting Tau into large amorphous aggregates. NMR data suggest that the D‐enantiomeric peptides bound to Tau monomers with rather low affinity, but ELISA (enzyme‐linked immunosorbent assay) data demonstrated binding to PHF6* and full length Tau fibrils. In addition, molecular insight into the binding mode of MMD3 to PHF6* fibrils were gained by in silico modelling. The identified PHF6*‐targeting peptides were able to penetrate cells. The study establishes PHF6* fibril binding peptides consisting of D‐enantiomeric amino acids as potential molecules for therapeutic and diagnostic applications in AD research. John Wiley and Sons Inc. 2021-09-12 2021-11-03 /pmc/articles/PMC8596876/ /pubmed/34375027 http://dx.doi.org/10.1002/cbic.202100287 Text en © 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Full Papers
Malhis, Marwa
Kaniyappan, Senthilvelrajan
Aillaud, Isabelle
Chandupatla, Ram Reddy
Ramirez, Lisa Marie
Zweckstetter, Markus
Horn, Anselm H. C.
Mandelkow, Eckhard
Sticht, Heinrich
Funke, Susanne Aileen
Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display
title Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display
title_full Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display
title_fullStr Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display
title_full_unstemmed Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display
title_short Potent Tau Aggregation Inhibitor D‐Peptides Selected against Tau‐Repeat 2 Using Mirror Image Phage Display
title_sort potent tau aggregation inhibitor d‐peptides selected against tau‐repeat 2 using mirror image phage display
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596876/
https://www.ncbi.nlm.nih.gov/pubmed/34375027
http://dx.doi.org/10.1002/cbic.202100287
work_keys_str_mv AT malhismarwa potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT kaniyappansenthilvelrajan potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT aillaudisabelle potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT chandupatlaramreddy potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT ramirezlisamarie potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT zweckstettermarkus potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT hornanselmhc potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT mandelkoweckhard potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT stichtheinrich potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay
AT funkesusanneaileen potenttauaggregationinhibitordpeptidesselectedagainsttaurepeat2usingmirrorimagephagedisplay