Abstract:
: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.
journal_name
EBioMedicinejournal_title
EBioMedicineauthors
Ruderisch N,Schlatter D,Kuglstatter A,Guba W,Huber S,Cusulin C,Benz J,Rufer AC,Hoernschemeyer J,Schweitzer C,Bülau T,Gärtner A,Hoffmann E,Niewoehner J,Patsch C,Baumann K,Loetscher H,Kitas E,Freskgård POdoi
10.1016/j.ebiom.2017.09.004subject
Has Abstractpub_date
2017-10-01 00:00:00pages
76-92issn
2352-3964pii
S2352-3964(17)30351-1journal_volume
24pub_type
杂志文章相关文献
EBioMedicine文献大全abstract:BACKGROUND:In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research. METHODS:To evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Ca...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102971
更新日期:2020-09-01 00:00:00
abstract::Warming temperatures may increase the geographic spread of vector-borne diseases into temperate areas. Although a tropical mosquito-borne viral disease, a dengue outbreak occurred in Madeira, Portugal, in 2012; the first in Europe since 1920s. This outbreak emphasizes the potential for dengue re-emergence in Europe gi...
journal_title:EBioMedicine
pub_type: 历史文章,杂志文章
doi:10.1016/j.ebiom.2016.03.046
更新日期:2016-05-01 00:00:00
abstract:BACKGROUND:Cancer of unknown primary (CUP), representing approximately 3-5% of all malignancies, is defined as metastatic cancer where a primary site of origin cannot be found despite a standard diagnostic workup. Because knowledge of a patient's primary cancer remains fundamental to their treatment, CUP patients are s...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.103030
更新日期:2020-11-01 00:00:00
abstract:BACKGROUND:Gastric cancer (GC) ranks the fifth most common cancer, and chemotherapy is one of the most common treatments for GC. However, chemoresistance limits the effectiveness of chemotherapy and leads to treatment failure. This study aims to investigate the biological effect of miR-567 on gastric tumourigenesis and...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.05.003
更新日期:2019-06-01 00:00:00
abstract:BACKGROUND:Glioblastoma (GBM), a highly malignant brain tumor, invariably recurs after therapy. Quiescent GBM cells represent a potential source of tumor recurrence, but little is known about their molecular underpinnings. METHODS:Patient-derived GBM cells were engineered by CRISPR/Cas9-assisted knock-in of an inducib...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.03.064
更新日期:2019-04-01 00:00:00
abstract:BACKGROUND:Recurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring. However, the possibility of detecting these mutations in cell-fre...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.05.004
更新日期:2019-06-01 00:00:00
abstract:BACKGROUND:Acute myeloid leukaemia (AML) is a malignant haematological tumour with high heterogeneity and mortality. A reliable prognostic assessment is critical for treatment strategies. However, the current prognostic evaluation system of AML is insufficient. METHODS:Genome-wide univariate Cox regression analysis wa...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102664
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected fi...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102675
更新日期:2020-03-01 00:00:00
abstract::The nascent field of 'Nutritional Psychiatry' offers much promise for addressing the large disease burden associated with mental disorders. A consistent evidence base from the observational literature confirms that the quality of individuals' diets is related to their risk for common mental disorders, such as depressi...
journal_title:EBioMedicine
pub_type: 杂志文章,评审
doi:10.1016/j.ebiom.2017.02.020
更新日期:2017-03-01 00:00:00
abstract::The transcription factor Bach1 impairs angiogenesis after ischemic injury by suppressing Wnt/β-catenin signaling; however, the specific domains responsible for the anti-angiogenic effects of Bach1 remain unclear. This study determined the role of the BTB domain of Bach1 in ischemic angiogenesis. Bach1 is highly expres...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.102617
更新日期:2020-01-01 00:00:00
abstract:BACKGROUND:Neurodegenerative diseases are incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in photoreceptor death and progresses to the loss of the entire retinal network. We previously found that proteomic analysis of the adja...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102636
更新日期:2020-02-01 00:00:00
abstract::Clear cell renal cell carcinoma (ccRCC) is the most lethal neoplasm of the urologic system. Clinical therapeutic effect varies greatly between individual ccRCC patients, so there is an urgent need to develop prognostic molecular biomarkers to help clinicians identify patients in need of early aggressive management. In...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2016.12.003
更新日期:2017-02-01 00:00:00
abstract:BACKGROUND:Corneal neovascularization (angiogenesis and lymphangiogenesis) compromises corneal transparency and transplant survival, however, the molecular mechanisms of corneal host epithelial and stromal cells in neovascularization have not yet been fully elucidated. Furthermore, the contribution and mechanism of cor...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.05.026
更新日期:2019-06-01 00:00:00
abstract::Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that curren...
journal_title:EBioMedicine
pub_type: 杂志文章,评审
doi:10.1016/j.ebiom.2017.01.042
更新日期:2017-02-01 00:00:00
abstract:BACKGROUND:Current methods of lymph node (LN) staging are controversial in predicting the survival of SBA. We aimed to develop an alternative LN-classification-based nomogram to individualize SBA prognosis. METHODS:Based on the data from the Surveillance, Epidemiology, and End Results (SEER) database of patients diagn...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2018.05.022
更新日期:2018-06-01 00:00:00
abstract:BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, mainly due to cigarette smoking, which represents the third cause of mortality worldwide. The mechanisms driving its epithelial salient features remain largely elusive. We aimed to evaluate the activation and the role of the canonica...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.103034
更新日期:2020-11-01 00:00:00
abstract:BACKGROUND:Intervertebral disc degeneration (IDD) is a major contributor to lower back pain, however, the molecular and pathogenetic mechanisms underlying IDD are poorly understood. As a high-risk factor for IDD, compression stress was reported to induce apoptosis of nucleus pulposus (NP) cells and extracellular matrix...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102679
更新日期:2020-03-01 00:00:00
abstract::Previous transcriptomic analyses suggested that the 1918 influenza A virus (IAV1918), one of the most devastating pandemic viruses of the 20th century, induces a dysfunctional cytokine storm and affects other innate immune response patterns. Because all viruses are obligate parasites that require host cells for replic...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2018.05.027
更新日期:2018-06-01 00:00:00
abstract:BACKGROUND:Subcellular localization and function of L-type calcium channels (LTCCs) play an important role in regulating contraction of cardiomyocytes. Understanding how this is affected by the disruption of transverse tubules during heart failure could lead to new insights into the disease. METHODS:Cardiomyocytes wer...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102845
更新日期:2020-07-01 00:00:00
abstract::The emergence and prevalence of antibiotic-resistant bacteria are an increasing cause of death worldwide, resulting in a global 'call to action' to avoid receding into an era lacking effective antibiotics. Despite the urgency, the healthcare industry still relies on a single in vitro bioassay to determine antibiotic e...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2017.05.026
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND:Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we ass...
journal_title:EBioMedicine
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.ebiom.2018.06.022
更新日期:2018-07-01 00:00:00
abstract:BACKGROUND:The development of an effective vaccine preventing HIV-1 infection is hindered by the enormous antigenic variability and unique biochemical and immunological properties of HIV-1 Env glycoprotein, the most promising target for HIV-1 neutralizing antibody. Functional studies of rare elite neutralizers led to t...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.07.015
更新日期:2019-09-01 00:00:00
abstract:BACKGROUND:Cisplatin resistance remains a major clinical obstacle to the successful treatment of non-small cell lung cancer (NSCLC). Scribble contributes to ROS-induced inflammation and cisplatin-elevated toxic reactive oxygen species (ROS) promotes cell death. However, it is unknown whether and how Scribble is involve...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.08.057
更新日期:2019-09-01 00:00:00
abstract::A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. H...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2017.08.028
更新日期:2017-10-01 00:00:00
abstract::Mesenchymal stem cell (MSC)-derived exosomes have diverse functions in regulating wound healing and inflammation; however, the molecular mechanism of human umbilical cord MSC (hUCMSC)-derived exosomes in regulating burn-induced inflammation is not well understood. We found that burn injury significantly increased the ...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2016.04.030
更新日期:2016-06-01 00:00:00
abstract::Tau is a major component of the neurofibrillary tangles (NFT) that represent a pathological hallmark of Alzheimer's disease (AD). Although generally considered an axonal protein, Tau is found in the somato-dendritic compartment of degenerating neurons and this redistribution is thought to be a trigger of neurodegenera...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2017.05.012
更新日期:2017-06-01 00:00:00
abstract::Disease-specific alterations of the cell-free DNA methylation status are frequently found in serum samples and are currently considered to be suitable biomarkers. Candidate markers were identified by bisulfite conversion-based genome-wide methylation screening of lung tissue from lung cancer, fibrotic ILD, and COPD. c...
journal_title:EBioMedicine
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.ebiom.2015.06.025
更新日期:2015-07-02 00:00:00
abstract:BACKGROUND:A newly developed drug trastuzumab emtansine (T-DM1) has improved the survival of breast cancer (BC) patients. Despite an impressive initial clinical response, a subgroup of patient develop resistance and present therapeutic challenges. The underlying resistance mechanisms are not fully investigated. We repo...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.04.061
更新日期:2019-05-01 00:00:00
abstract:BACKGROUND:We aimed to identify a magnetic resonance imaging (MRI)-based model for assessment of the risk of individual distant metastasis (DM) before initial treatment of nasopharyngeal carcinoma (NPC). METHODS:This retrospective cohort analysis included 176 patients with NPC. Using the PyRadiomics platform, we extra...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.01.013
更新日期:2019-02-01 00:00:00
abstract:BACKGROUND:Sphingomyelin synthase 1 (SMS1) has been reported to participate in hepatitis and atherosclerosis. However, its role in autoimmune response is not clear. This study investigates the possible involvement of SMS1 in B-cell activation and lupus-like autoimmunity. METHODS:SMS1 knockout lupus-like animal model a...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.06.038
更新日期:2019-07-01 00:00:00