Epitope Scaffolding using Alpha-synuclein Cyclic Peptides to Generate Oligomer-selective Antibodies for Parkinson's Disease

Speaker: Shaen Hsueh

Date: Mon, Jun 28, 2021 to Tue, Jun 29, 2021

Location: Online

Conference: 2021 Frontiers in Biophysics

Subject: Mathematics

Class: Scientific


Effectively scaffolding epitopes on immunogens, in order to raise conformationally selective antibodies through active immunization, is a central problem in treating protein misfolding diseases, particularly neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. We seek to selectively target conformations enriched in toxic, oligomeric propagating species while sparing healthy forms of the protein which are often more abundant. To this end, we scaffolded cyclic peptides by varying the number of flanking glycines, to best mimic a misfolding-specific conformation of an epitope of alpha-synuclein enriched in the oligomer ensemble, as characterized by a region most readily disordered and solventexposed in a stressed, partially denatured protofibril. We screen and rank the cyclic peptide scaffolds of alpha-synuclein in silico based on their ensemble overlap properties with the fibril, oligomer-model, and isolated monomer ensembles. We introduce a method for screening against structured off-pathway targets in the human proteome, by selecting scaffolds with minimal conformational similarity between their epitope and the same primary sequence in structured human proteins. Ensemble comparison and overlap was quantified by the Jensen-Shannon Divergence, and a new measure introduced here---the embedding depth, which determines the extent to which a given ensemble is subsumed by another ensemble, and which may be a more useful measure in sculpting the conformational-selectivity of an antibody.

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