Developing Glycine-rich Peptide Therapeutics Targeting Alpha-Synuclein Aggregation in Parkinson Disease
Disciplines
Biochemistry | Medicinal-Pharmaceutical 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, affecting also the lives of their families, friends, and caregivers by causing memory loss, behavioral changes, and social reclusion, which progressively get worse over time. In recent studies, scientists have uncovered a link between alpha-synuclein (α-syn) and Parkinson’s disease. The misfolding and aggregation of alpha-synuclein, often called Lewy Bodies (LB), is extremely hard to exterminate, which suggests for 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, a disadvantage of small molecules. Furthermore, their amino-acid-based structure minimizes the risk of eliciting an immune response. This study aims to design glycine-rich peptide analogs to inhibit alpha-synuclein aggregation. By utilizing alpha-fold, 3D models of the ten peptide analogs were created. Subsequently using the molecular docking, the binding affinity of each of these analogs was determined. Among these analogs, one analog was synthesized using the solid phase synthesis protocol. In this protocol, high swelling rink amide resin with a loading capacity of 0.6 mmol/g and 100-200 mesh size was used. The peptide-resin complexes were cleaved, filtered and precipitated. Then, the precipitate dissolved with 10% acetic acid and lyophilized overnight to form peptide powders. The peptide was characterized by mass spectrometry. One intense peak was noticed at m/z 503.3 which corresponds to [M+2H]2+, change states which exactly agreed with the theoretical masses. For further studies, biological assay using LCMS and FRET will be employed to measure the inhibition efficiency of these peptides.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Developing Glycine-rich Peptide Therapeutics Targeting Alpha-Synuclein Aggregation in Parkinson 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, affecting also the lives of their families, friends, and caregivers by causing memory loss, behavioral changes, and social reclusion, which progressively get worse over time. In recent studies, scientists have uncovered a link between alpha-synuclein (α-syn) and Parkinson’s disease. The misfolding and aggregation of alpha-synuclein, often called Lewy Bodies (LB), is extremely hard to exterminate, which suggests for 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, a disadvantage of small molecules. Furthermore, their amino-acid-based structure minimizes the risk of eliciting an immune response. This study aims to design glycine-rich peptide analogs to inhibit alpha-synuclein aggregation. By utilizing alpha-fold, 3D models of the ten peptide analogs were created. Subsequently using the molecular docking, the binding affinity of each of these analogs was determined. Among these analogs, one analog was synthesized using the solid phase synthesis protocol. In this protocol, high swelling rink amide resin with a loading capacity of 0.6 mmol/g and 100-200 mesh size was used. The peptide-resin complexes were cleaved, filtered and precipitated. Then, the precipitate dissolved with 10% acetic acid and lyophilized overnight to form peptide powders. The peptide was characterized by mass spectrometry. One intense peak was noticed at m/z 503.3 which corresponds to [M+2H]2+, change states which exactly agreed with the theoretical masses. For further studies, biological assay using LCMS and FRET will be employed to measure the inhibition efficiency of these peptides.