Stabilization of amyloidogenic immunoglobulin light chains by small molecules

Gareth J. Morgan, Nicholas L. Yan, David E. Mortenson, Enrico Rennella, Joshua M. Blundon, Ryan M. Gwin, Chung Yon Lin, Robyn L. Stanfield, Steven J. Brown, Hugh Rosen, Timothy P. Spicer, Virneliz Fernandez-Vega, Giampaolo Merlini, Lewis E. Kay, Ian A. Wilson, Jeffery W. Kelly

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)8360-8369
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number17
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Dimerization
  • High-throughput screen
  • Kinetic stabilizer
  • Proteotoxicity
  • Structural biology

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Stabilization of amyloidogenic immunoglobulin light chains by small molecules'. Together they form a unique fingerprint.

  • Cite this

    Morgan, G. J., Yan, N. L., Mortenson, D. E., Rennella, E., Blundon, J. M., Gwin, R. M., Lin, C. Y., Stanfield, R. L., Brown, S. J., Rosen, H., Spicer, T. P., Fernandez-Vega, V., Merlini, G., Kay, L. E., Wilson, I. A., & Kelly, J. W. (2019). Stabilization of amyloidogenic immunoglobulin light chains by small molecules. Proceedings of the National Academy of Sciences of the United States of America, 116(17), 8360-8369. https://doi.org/10.1073/pnas.1817567116