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Protein-catalyzed capture agents targeting misfolded superoxide dismutase 1

Atsavapranee, Beatriz and Bunck, David and Museth, Katrine and Vander Velde, David and Heath, James (2017) Protein-catalyzed capture agents targeting misfolded superoxide dismutase 1. In: 254th American Chemical Society National Meeting & Exposition, August 20-24, 2017, Washington, DC. https://resolver.caltech.edu/CaltechAUTHORS:20170912-074421755

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons in the brain and spinal cord. Familial ALS can be caused by mutant isoforms of superoxide dismutase 1 (SOD1) that lead the protein to misfold and adopt toxic conformations. Over 180 mutations in SOD1 are linked to the disease, making it a challenging therapeutic target. Protein-catalyzed capture (PCC) agents are ligands assembled through in situ click chem. that can bind a protein to stabilize its native conformation. The objective of this project is to develop PCC agents that target SOD1 mutants and reduce misfolding. We used an epitope-targeted screen to identify oligopeptides that bind the electrostatic loop (a region of the protein destabilized upon mutation) and an internal fragment (revealed upon misfolding). We anticipate that the PCC agents against the internal fragment and precleared against the electrostatic loop will bind misfolded SOD1 selectively, while the PCC agents against the electrostatic loop will detect folded SOD1. This will allow us to discriminate between the folded and misfolded species. Screens against the electrostatic loop yielded a PCC agent with promising ability to recognize SOD1. Ultimately, this ligand might be used to mitigate aggregation of mutant isoforms and treat ALS.


Item Type:Conference or Workshop Item (Paper)
Related URLs:
URLURL TypeDescription
https://www.acs.org/content/acs/en/meetings/fall-2017.htmlOrganizationConference Website
ORCID:
AuthorORCID
Heath, James0000-0001-5356-4385
Additional Information:© 2017 American Chemical Society.
Record Number:CaltechAUTHORS:20170912-074421755
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170912-074421755
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:81335
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Sep 2017 16:24
Last Modified:03 Oct 2019 18:41

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