Stabilization of amyloidogenic immunoglobulin light chains by small molecules.
dimerization
high-throughput screen
kinetic stabilizer
proteotoxicity
structural biology
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
23 04 2019
23 04 2019
Historique:
pubmed:
12
4
2019
medline:
26
3
2020
entrez:
12
4
2019
Statut:
ppublish
Résumé
In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC-LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.
Identifiants
pubmed: 30971495
pii: 1817567116
doi: 10.1073/pnas.1817567116
pmc: PMC6486714
doi:
Substances chimiques
Amyloid
0
Immunoglobulin Light Chains
0
Banques de données
PDB
['6MG4', '6MG5']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
8360-8369Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK046335
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK046335
Pays : United States
Organisme : NIH HHS
ID : S10 OD012289
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002550
Pays : United States
Déclaration de conflit d'intérêts
Conflict of interest statement: G.J.M., N.L.Y., and J.W.K. have submitted a patent application for the small-molecule kinetic stabilizers of Ig light chains.
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