Stabilization of amyloidogenic immunoglobulin light chains by small molecules

Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8360-8369. doi: 10.1073/pnas.1817567116. Epub 2019 Apr 10.

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.

Keywords: dimerization; high-throughput screen; kinetic stabilizer; proteotoxicity; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid* / chemistry
  • Amyloid* / metabolism
  • Amyloidosis
  • High-Throughput Screening Assays
  • Humans
  • Immunoglobulin Light Chains* / chemistry
  • Immunoglobulin Light Chains* / metabolism
  • Kinetics
  • Protein Multimerization
  • Protein Stability*

Substances

  • Amyloid
  • Immunoglobulin Light Chains

Associated data

  • PDB/6MG4
  • PDB/6MG5