Design and Development of Peptide Inhibitors Targeting Alpha-Synuclein for Parkinson’s Disease

Author

• Zainab Noor, Kennesaw State UniversityFollow

Semester of Graduation

Spring 2026

Degree Type

Thesis

Degree Name

Master of Science

Department

Department of Chemistry and Biochemistry

Committee Chair/First Advisor

Mohammad Halim

Second Advisor

Wei Zhou

Third Advisor

Madalynn Marshall

Abstract

Parkinson’s disease is a progressive neurodegenerative disorder affecting about 6.9 million adults over 65, with projections reaching 14.2 million by 2040, marked by the pathological aggregation of an intrinsically disordered protein α-synuclein. Currently, therapies exist to improve symptoms but do not slow or halt disease progression. Peptide-based therapeutics offer a promising alternative, particularly as inhibitors of α-synuclein aggregation—due to their high selectivity, better tolerability, and reduced adverse effects. This study aimed to design, synthesize, and evaluate peptides with inhibitory potential. Several peptides were initially screened using computational tools to predict binding interactions with α-synuclein. Top five candidates with favorable docking scores were synthesized via SPPS and characterized by LC-MS. Binding affinities were quantified using Selected Ion Monitoring Assay (SIM-LCMS), which confirmed strong peptide–protein interactions. Three peptides showed nanomolar affinity with dissociation constants (Kd) of 22.98, 51.79 and 160.4 nM. Structurally modified analogues were also evaluated, where α-methylated peptide exhibited the strongest binding (Kd = 21.49 nM). Inhibition of α-synuclein fibrillation was assessed using thioflavin T (ThT) fluorescence assay. After four days of incubation, the α-methylated peptide achieved the highest inhibition, reducing fibril formation to 89.2% compared to 80.3%, 66.6%, and 41.1% for other candidates respectively. These results validate computational predictions and highlight methylation-enhanced peptide drug discovery against α-synuclein aggregation. The combined SIM-LCMS and ThT assay results provide proof-of-concept that peptide inhibitors can modulate α-synuclein fibril formation with nanomolar affinity. Future work will focus on improving stability and activity through structural modifications such as cyclization and targeted methylation.