Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport
Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417303511 |
| _version_ | 1829509314410184704 |
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| author | Nadine Ruderisch Daniel Schlatter Andreas Kuglstatter Wolfgang Guba Sylwia Huber Carlo Cusulin Jörg Benz Arne Christian Rufer Joerg Hoernschemeyer Christophe Schweitzer Tina Bülau Achim Gärtner Eike Hoffmann Jens Niewoehner Christoph Patsch Karlheinz Baumann Hansruedi Loetscher Eric Kitas Per-Ola Freskgård |
| author_facet | Nadine Ruderisch Daniel Schlatter Andreas Kuglstatter Wolfgang Guba Sylwia Huber Carlo Cusulin Jörg Benz Arne Christian Rufer Joerg Hoernschemeyer Christophe Schweitzer Tina Bülau Achim Gärtner Eike Hoffmann Jens Niewoehner Christoph Patsch Karlheinz Baumann Hansruedi Loetscher Eric Kitas Per-Ola Freskgård |
| author_sort | Nadine Ruderisch |
| collection | DOAJ |
| description | Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance. |
| first_indexed | 2024-12-16T11:43:16Z |
| format | Article |
| id | doaj.art-316ddf067d1746b19366ae2a8f354fcb |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-16T11:43:16Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-316ddf067d1746b19366ae2a8f354fcb2022-12-21T22:32:53ZengElsevierEBioMedicine2352-39642017-10-0124C769210.1016/j.ebiom.2017.09.004Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle TransportNadine Ruderisch0Daniel Schlatter1Andreas Kuglstatter2Wolfgang Guba3Sylwia Huber4Carlo Cusulin5Jörg Benz6Arne Christian Rufer7Joerg Hoernschemeyer8Christophe Schweitzer9Tina Bülau10Achim Gärtner11Eike Hoffmann12Jens Niewoehner13Christoph Patsch14Karlheinz Baumann15Hansruedi Loetscher16Eric Kitas17Per-Ola Freskgård18Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Munich, GermanyPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Munich, GermanyPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Munich, GermanyPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, SwitzerlandPharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, SwitzerlandTherapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.http://www.sciencedirect.com/science/article/pii/S2352396417303511BACE1Alzheimer's diseaseBlood brain barrierCNS delivery |
| spellingShingle | Nadine Ruderisch Daniel Schlatter Andreas Kuglstatter Wolfgang Guba Sylwia Huber Carlo Cusulin Jörg Benz Arne Christian Rufer Joerg Hoernschemeyer Christophe Schweitzer Tina Bülau Achim Gärtner Eike Hoffmann Jens Niewoehner Christoph Patsch Karlheinz Baumann Hansruedi Loetscher Eric Kitas Per-Ola Freskgård Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport EBioMedicine BACE1 Alzheimer's disease Blood brain barrier CNS delivery |
| title | Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |
| title_full | Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |
| title_fullStr | Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |
| title_full_unstemmed | Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |
| title_short | Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport |
| title_sort | potent and selective bace 1 peptide inhibitors lower brain aβ levels mediated by brain shuttle transport |
| topic | BACE1 Alzheimer's disease Blood brain barrier CNS delivery |
| url | http://www.sciencedirect.com/science/article/pii/S2352396417303511 |
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