Synthesis, Characterization and Fibril Reduction Assay of Glycine-rich Peptide Targeting Alpha-Synuclein Aggregation in Parkinson’s Disease
Disciplines
Medicinal-Pharmaceutical Chemistry | Organic Chemistry
Abstract (300 words maximum)
Various neurodegenerative conditions like dementia, Alzheimer’s disease (AD), and Parkinson’s disease (PD) cannot be easily treated using current medical technology. Currently, over 55 million individuals suffer from dementia worldwide, with more than 10 million new cases diagnosed every year. The impact of dementia extends far beyond the individual, also affecting the lives of their families, friends, and caregivers by causing memory loss, behavioral changes, and social reclusion. In recent studies, scientists have uncovered a link between alpha-synuclein (α-syn) and Parkinson’s disease. The misfolding and aggregation of alpha-synuclein are extremely difficult to eradicate, which suggests a new therapeutic strategy. As a result of their high target specificity and potency, peptide therapeutics are designed to bind specifically to certain proteins or receptors, leading to enhanced efficacy and minimizing the risk of eliciting immune responses, a disadvantage of small-molecule drugs. This study aims to design glycine-rich peptide analogs to inhibit alpha-synuclein aggregation. A series of analogs was computationally designed. Subsequently, using molecular docking, the binding affinity with the alpha-synuclein protein was determined for each analog. Based on the docking score, four analogs were synthesized using solid-phase peptide synthesis protocol. In this protocol, high swelling rink amide resin (ProTide) with a loading capacity of 0.58 –0.60 mmol/g and 100-200 mesh size was used. The resin-peptide complexes were then cleaved using a cocktail containing a high concentration of trifluoroacetic acid (TFA). The cleaved peptides were filtered and precipitated using cold ether. Analogs 5, 6, 8, and 10 were characterized by LCMS. For analog 8, one intense peak was noticed at m/z 707.40, which corresponds to [M+H]+. For analog 10, one intense peak was detected at m/z 503.3, which corresponds to [M+2H]2+. Both agreed with theoretical mass. These peptides also significantly reduced (91.41%) the in-vitro fibril formation of alpha-synuclein.
Use of AI Disclaimer
no
Academic department under which the project should be listed
CSM – Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Synthesis, Characterization and Fibril Reduction Assay of Glycine-rich Peptide Targeting Alpha-Synuclein Aggregation in Parkinson’s Disease
Various neurodegenerative conditions like dementia, Alzheimer’s disease (AD), and Parkinson’s disease (PD) cannot be easily treated using current medical technology. Currently, over 55 million individuals suffer from dementia worldwide, with more than 10 million new cases diagnosed every year. The impact of dementia extends far beyond the individual, also affecting the lives of their families, friends, and caregivers by causing memory loss, behavioral changes, and social reclusion. In recent studies, scientists have uncovered a link between alpha-synuclein (α-syn) and Parkinson’s disease. The misfolding and aggregation of alpha-synuclein are extremely difficult to eradicate, which suggests a new therapeutic strategy. As a result of their high target specificity and potency, peptide therapeutics are designed to bind specifically to certain proteins or receptors, leading to enhanced efficacy and minimizing the risk of eliciting immune responses, a disadvantage of small-molecule drugs. This study aims to design glycine-rich peptide analogs to inhibit alpha-synuclein aggregation. A series of analogs was computationally designed. Subsequently, using molecular docking, the binding affinity with the alpha-synuclein protein was determined for each analog. Based on the docking score, four analogs were synthesized using solid-phase peptide synthesis protocol. In this protocol, high swelling rink amide resin (ProTide) with a loading capacity of 0.58 –0.60 mmol/g and 100-200 mesh size was used. The resin-peptide complexes were then cleaved using a cocktail containing a high concentration of trifluoroacetic acid (TFA). The cleaved peptides were filtered and precipitated using cold ether. Analogs 5, 6, 8, and 10 were characterized by LCMS. For analog 8, one intense peak was noticed at m/z 707.40, which corresponds to [M+H]+. For analog 10, one intense peak was detected at m/z 503.3, which corresponds to [M+2H]2+. Both agreed with theoretical mass. These peptides also significantly reduced (91.41%) the in-vitro fibril formation of alpha-synuclein.