P2-051: IN VITRO ASSAY TO ASSESS THE POTENTIAL OF SEA BUCKTHORN AND GOJI BERRY AS THERAPEUTIC AGENTS FOR ALZHEIMER'S DISEASE

So far, there is no effective disease-modifying therapies for Alzheimer’s Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.

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Identifying Novel Candidates for Re-Purposing as Potential Therapeutic Agents for Alzheimer’s disease

10.1101/622308 ◽

2019 ◽

Author(s):

C Ballard ◽

B Creese ◽

A Gatt ◽

P Doherty ◽

PT Francis ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inverse Correlation ◽

Therapeutic Agents ◽

Potential Treatment ◽

Significant Inverse Correlation ◽

Expression Studies ◽

Screening Assays ◽

Meta Analyses

AbstractThe current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimer’s disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.

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Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 inhibitor: Plausible lead for Alzheimer’s Disease.

Medicinal Chemistry ◽

10.2174/1573406417666201221155452 ◽

2020 ◽

Vol 17 ◽

Author(s):

Priti Jain ◽

Pankaj K Wadhwa ◽

Hemant R Jadhav

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Aromatic Ring ◽

Active Sites ◽

Neurodegenerative Disorder ◽

Pyrimidine Derivatives ◽

Vitro Assay ◽

Docking Score ◽

Bace 1

: Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer’s disease (AD). Since, it catalyzes the rate limiting step of Aβ-42 production from amyloid precursor protein (APP),its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group. Objective: Design and synthesis of 2,4,6-substituted pyrimidine derivatives has been reported. In vitro FRET based screening of synthesized derivatives was performed to evaluate the BACE-1 inhibition profile. Method: Based on the docking simulation studies, a library of derivatives was designed, synthesized and evaluated for BACE-1 inhibition in-vitro. The docking studies were performed on Glide (Schrodinger suite) and Molegro virtual docker. Theoretical toxicity was predicted using Osiris Property Explorer. The synthesized compounds were tested for BACE-1 inhibition using in vitro assay based on Fluorescence Resonance Energy Transfer technique. The percent inhibition was calculated as a measure of activity. Results: The designed compounds revealed strong interactions with the desired amino acids of BACE-1 active sites. The aromatic rings placed at fourth and sixth position of pyrimidine ring occupied S1 and S3 substrate binding clefts while the amino group formed hydrogen bonding interactions with Asp32 and Asp228. In silico data ensured that the compounds were orally bioavailable and brain permeable. The in vitro testing showed that the compounds inhibited BACE-1 at 10µM concentration. Conclusion: Compounds substituted with m-benzyloxy on one aromatic ring and o,p-di-chloro on another aromatic ring displayed maximum BACE-1 inhibition. Compound 2.13A displayed high docking score and was found to be most potent with IC50 of 6.92µM. The series displayed a good correlation between docking score and BACE-1 inhibition profile.

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In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer’s Disease

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555217697964 ◽

2017 ◽

Vol 22 (6) ◽

pp. 676-685 ◽

Cited By ~ 3

Author(s):

Laura Aitken ◽

Gemma Baillie ◽

Andrew Pannifer ◽

Angus Morrison ◽

Philip S. Jones ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Throughput Screening ◽

Amyloid Β ◽

Metabolic Enzyme ◽

Amyloid Β Peptide ◽

Vitro Assay ◽

Screening Platform ◽

Potential Inhibitors

A major hallmark of Alzheimer’s disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.

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