Synthesis of Linear and Cyclic Peptides to Inhibit the Aggregation of Alpha-Synuclein in Parkinson’s Disease

Parkinsons (PD) is a neurological disease that is caused by the buildup of Lewy bodies in neurons. PD is the second highest diagnosed neurological disease in the United States with 90,000 people being diagnosed a year. Alpha-Synuclein easily misfolds and is the main protein in Lewy bodies. Peptide therapeutics can be used to delay effects or even to cure the disease. In this study, 4554w peptide and its cysteine based cyclic derivatives was synthesized. The cyclic analogue of this peptide was synthesized in hopes of potentially finding a better candidate and furthering research since cyclic peptides are more stable compared to linear peptide. Standard Fmoc solid phase peptide synthesis protocols by CEM Liberty Blue peptide synthesizer were used to synthesize the linear peptides. Both peptide-resin complexes were cleavage using 95% trifluoracetic acid and heated at 42°C in the water bath for 30 mins. Peptides were filtered and precipitated with cold diethyl ether. Peptide characterization was then conducted with Mass spectrometry. The linear peptide shows two strong peaks at m/z 500.83 and 999.92 which correspond to doubly and singly charge states. Two cysteine amino acids was added in the N-terminal and C-terminal of 4554w peptide and cyclization reaction was performed by adding 10% DMSO and stirring over 48 hours. This would display a change in mass as cyclization results in the loss of 2 hydrogens while gaining a disulfide bond between cystines, which was supported with mass spectrometry results. Further research will be conducted on the interaction of these peptides with Alpha-Synuclein employing native mass spectrometry techniques