Development of Peptide Therapeutics to Reduce Fibril Formation of Alpha-Synuclein in Parkinson Disease
Disciplines
Medicinal-Pharmaceutical Chemistry | Organic Chemistry
Abstract (300 words maximum)
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide and the fastest growing in terms of death and disability, as reported by the World Health Organization. The disease is driven by the progressive loss of dopaminergic neurons in the substantia nigra, primarily caused by the aggregation of misfolded α-synuclein into oligomers and fibrils that form Lewy bodies. These aggregates disrupt neuronal function, impair motor control, and lead to cognitive decline. Current PD treatments are largely symptomatic and do not address the molecular pathology, highlighting the need for disease-modifying therapeutics. This study aimed to design and evaluate peptide analogs capable of binding to α-synuclein and inhibiting its aggregation. Previously computational modeling was employed to design and screen multiple analogs based on theoretical binding affinity and strong interaction between peptide and Alpha Synuclein. The top analog 8 (AP8) and parent peptide (PP) were synthesized using solid-phase peptide synthesis (SPPS) and verified with liquid chromatography and mass spectrometry. The binding assay revealed that both peptides significantly reduced α-synuclein oligomerization and fibril formation compared to controls, with AP8 showing superior efficacy. In addition, AP8 exhibited a dissociation constant (Kd) of 018.89 nanomolar (nM) indicating strong binding affinity and achieved a 67% reduction in fibril formation. These findings underscore the potential of structure-guided peptide optimization to inhibit α-synuclein aggregation.
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Academic department under which the project should be listed
CSM – Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Development of Peptide Therapeutics to Reduce Fibril Formation of Alpha-Synuclein in Parkinson Disease
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide and the fastest growing in terms of death and disability, as reported by the World Health Organization. The disease is driven by the progressive loss of dopaminergic neurons in the substantia nigra, primarily caused by the aggregation of misfolded α-synuclein into oligomers and fibrils that form Lewy bodies. These aggregates disrupt neuronal function, impair motor control, and lead to cognitive decline. Current PD treatments are largely symptomatic and do not address the molecular pathology, highlighting the need for disease-modifying therapeutics. This study aimed to design and evaluate peptide analogs capable of binding to α-synuclein and inhibiting its aggregation. Previously computational modeling was employed to design and screen multiple analogs based on theoretical binding affinity and strong interaction between peptide and Alpha Synuclein. The top analog 8 (AP8) and parent peptide (PP) were synthesized using solid-phase peptide synthesis (SPPS) and verified with liquid chromatography and mass spectrometry. The binding assay revealed that both peptides significantly reduced α-synuclein oligomerization and fibril formation compared to controls, with AP8 showing superior efficacy. In addition, AP8 exhibited a dissociation constant (Kd) of 018.89 nanomolar (nM) indicating strong binding affinity and achieved a 67% reduction in fibril formation. These findings underscore the potential of structure-guided peptide optimization to inhibit α-synuclein aggregation.