Design and Development of Peptide Therapeutics Targeting the Alpha-Synuclein Fibrils in Parkinson Disease
Disciplines
Biochemistry | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Parkinson’s Disease (PD) has the highest rate of increased death and disability of any neurological disorder, as well as being the second most prevalent neurological degenerative disease in the world according to the WHO. The symptoms are derived from the build-up of Lewy bodies (LB) leading to neuron degeneration, affecting both motor functions and memory recollection. Alpha-Synuclein protein is believed to be one of the sources for oligomerization and fibril formation. The aim of this research is to design and develop peptide analogs targeting alpha-synuclein to prevent oligomerization and fibril formation. Various analogs were computationally designed from a potent peptide to improve the crossing of blood-brain barrier and oral bioavailability. Molecular docking was employed to determine the binding affinity and interaction with Alpha-Synuclein. The peptides had docking scores ranging from -146.79 to -130.46. Analog 8 (-146.79) containing two phenylalanine in a helical turn showed the highest binding affinity and interaction at the docking sites. Based on the modelling results, this peptide was synthesized using the solid phase synthesis protocol using Liberty Blue peptide synthesizer. In this protocol, a high swelling rink-amide resin with a loading capacity of .6 mmol/g and 100-200 mesh size was used. After the peptide synthesis, the peptide-resin complexes were cleaved with a cocktail containing high amount of trifluoracetic acid. The cleaved peptides were filtered and precipitated by adding cold ether. Then, the precipitate dissolved with acetic acid and freeze-dried overnight to form peptide powders. The synthesis of the peptide was confirmed by mass spectrometry. Three intense peaks were detected at m/z 406.23, 608.83, and 1216.66 which correspond to [M+3H]3+, [M+2H]2+, and [M+H]1+ charge states, respectively. The experimental mass is precisely agreed with the theoretical mass of the peptide. In future, biological assays of this and other favorable peptides will be carried out.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Design and Development of Peptide Therapeutics Targeting the Alpha-Synuclein Fibrils in Parkinson Disease
Parkinson’s Disease (PD) has the highest rate of increased death and disability of any neurological disorder, as well as being the second most prevalent neurological degenerative disease in the world according to the WHO. The symptoms are derived from the build-up of Lewy bodies (LB) leading to neuron degeneration, affecting both motor functions and memory recollection. Alpha-Synuclein protein is believed to be one of the sources for oligomerization and fibril formation. The aim of this research is to design and develop peptide analogs targeting alpha-synuclein to prevent oligomerization and fibril formation. Various analogs were computationally designed from a potent peptide to improve the crossing of blood-brain barrier and oral bioavailability. Molecular docking was employed to determine the binding affinity and interaction with Alpha-Synuclein. The peptides had docking scores ranging from -146.79 to -130.46. Analog 8 (-146.79) containing two phenylalanine in a helical turn showed the highest binding affinity and interaction at the docking sites. Based on the modelling results, this peptide was synthesized using the solid phase synthesis protocol using Liberty Blue peptide synthesizer. In this protocol, a high swelling rink-amide resin with a loading capacity of .6 mmol/g and 100-200 mesh size was used. After the peptide synthesis, the peptide-resin complexes were cleaved with a cocktail containing high amount of trifluoracetic acid. The cleaved peptides were filtered and precipitated by adding cold ether. Then, the precipitate dissolved with acetic acid and freeze-dried overnight to form peptide powders. The synthesis of the peptide was confirmed by mass spectrometry. Three intense peaks were detected at m/z 406.23, 608.83, and 1216.66 which correspond to [M+3H]3+, [M+2H]2+, and [M+H]1+ charge states, respectively. The experimental mass is precisely agreed with the theoretical mass of the peptide. In future, biological assays of this and other favorable peptides will be carried out.