Small Dimer Peptide Therapeutics Targeting Beta Amyloid Fibrils in Alzheimer's Disease
Disciplines
Medicinal-Pharmaceutical Chemistry | Organic Chemistry
Abstract (300 words maximum)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia, responsible for up to 70% of dementia cases. Memory loss, impaired judgement, and mood changes, to name a few symptoms, are a result of AD. AD is characterized by neurofibrillary tangles and amyloid plaques that form spontaneously due to beta amyloid (Aβ) in the brain, according to the widely accepted amyloid hypothesis. The development of Aβ-peptide analogues is an effort to prevent fibril tangles, as these peptides are expected to bind to Aβ, thus disrupting fibril formation. The goal of this study is to develop monomeric and dimeric Aβ-derived peptides and compare their affinities for Aβ and the ability to inhibit fibril formation. It is expected that peptide dimers will exhibit high binding affinity to Aβ and will disrupt fibril formation. Four small monomeric peptides were synthesized using solid-phase peptide synthesis protocol employing Liberty Blue peptide synthesizer. In the protocol, a rink-amide based high-swelling resin with a loading capacity of 0.58 mmol/g and a mesh size of 115, was used for synthesis. After synthesis, peptides were cleaved from the resin using a cocktail solution containing copious amounts of trifluoracetic acid. The cleaved peptide was filtered and precipitated from solution using cold ether. Peptides are then freeze-dried to a powder-like form for analysis. Liquid chromatography-mass spectrometry (LC-MS) is used to confirm purity and mass of the peptides. For the monomer peptide AD1 (KLVFWAK), revealed two prominent peaks at m/z 445.77 and 890.54 corresponding to [M+2H]2+ and [M+H]+, respectively. AD2 (RGKLVFFGK), AD3(LPYFD) and AD4(LPFFN) were also successfully synthesized. A dimer peptide (KLVFWA)2K was also synthesized successfully. A similar procedure will be followed to develop other dimer peptides, and they will then be assessed for their ability to bind to Aβ and reduce fibril formation.
Use of AI Disclaimer
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Academic department under which the project should be listed
CSM – Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Small Dimer Peptide Therapeutics Targeting Beta Amyloid Fibrils in Alzheimer's Disease
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia, responsible for up to 70% of dementia cases. Memory loss, impaired judgement, and mood changes, to name a few symptoms, are a result of AD. AD is characterized by neurofibrillary tangles and amyloid plaques that form spontaneously due to beta amyloid (Aβ) in the brain, according to the widely accepted amyloid hypothesis. The development of Aβ-peptide analogues is an effort to prevent fibril tangles, as these peptides are expected to bind to Aβ, thus disrupting fibril formation. The goal of this study is to develop monomeric and dimeric Aβ-derived peptides and compare their affinities for Aβ and the ability to inhibit fibril formation. It is expected that peptide dimers will exhibit high binding affinity to Aβ and will disrupt fibril formation. Four small monomeric peptides were synthesized using solid-phase peptide synthesis protocol employing Liberty Blue peptide synthesizer. In the protocol, a rink-amide based high-swelling resin with a loading capacity of 0.58 mmol/g and a mesh size of 115, was used for synthesis. After synthesis, peptides were cleaved from the resin using a cocktail solution containing copious amounts of trifluoracetic acid. The cleaved peptide was filtered and precipitated from solution using cold ether. Peptides are then freeze-dried to a powder-like form for analysis. Liquid chromatography-mass spectrometry (LC-MS) is used to confirm purity and mass of the peptides. For the monomer peptide AD1 (KLVFWAK), revealed two prominent peaks at m/z 445.77 and 890.54 corresponding to [M+2H]2+ and [M+H]+, respectively. AD2 (RGKLVFFGK), AD3(LPYFD) and AD4(LPFFN) were also successfully synthesized. A dimer peptide (KLVFWA)2K was also synthesized successfully. A similar procedure will be followed to develop other dimer peptides, and they will then be assessed for their ability to bind to Aβ and reduce fibril formation.