Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2010.11.042 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Sertraline as a Multi-Target Modulator of AChE, COX-2, BACE-1, and GSK-3β: Computational and In Vivo Studies.
Molecules
November 2024
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia.
Alzheimer's disease (AD) is a neurodegenerative disorder associated with the dysregulation of several key enzymes, including acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2), glycogen synthase kinase 3β (GSK-3β), β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), and caspase-3. In this study, machine learning algorithms such as Random Forest (RF), Gradient Boost (GB), and Extreme Gradient Boost (XGB) were employed to screen US-FDA approved drugs from the ZINC15 database to identify potential dual inhibitors of COX-2 and AChE. The models were trained using molecules obtained from the ChEMBL database, with 5039 molecules for AChE and 3689 molecules for COX-2.
View Article and Find Full Text PDFTherapeutic Potential of Ramalin Derivatives with Enhanced Stability in the Treatment of Alzheimer's Disease.
Molecules
November 2024
Division of Polar Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea.
Alzheimer's disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent.
View Article and Find Full Text PDFIn Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.
Int J Mol Sci
September 2024
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test.
View Article and Find Full Text PDFBioactive compounds and in vitro biological properties of Arthrospira platensis and Athrospira maxima: a comparative study.
Sci Rep
October 2024
Food and Nutrition Academic and Research Cluster, Institute of Nutrition, Mahidol University, Salaya, Phuttamonthon, Nakhon Pathom, 73170, Thailand.
Article Synopsis
- Cyanobacteria, particularly the species Arthrospira, are rich in nutrients and natural pigments with numerous health benefits, prompting a study to optimize their extraction for maximum phenolic content and antioxidant activity.
- Through specific methods, the research determined effective extraction conditions that enhanced the yield of beneficial compounds, with A. maxima outperforming A. platensis in terms of bioactive content and enzyme inhibition properties.
- The study reveals that both species can inhibit key enzymes related to diseases like diabetes and Alzheimer's, with a notable synergy found between Arthrospira extracts and the Alzheimer's drug donepezil in inhibiting a critical enzyme linked to the disease.
Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro.
AAPS J
September 2024
Department of Pharmaceutics, Ernest Mario School of Pharmacy, the State University of New Jersey, 160 Frelinghuysen Road, Rutgers, Piscataway, NJ, 08854, USA.
β-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid β (Aβ) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aβ levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!