Stabilization of amyloidogenic immunoglobulin light chains by small molecules

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

doi:10.1073/pnas.1817567116

Stabilization of amyloidogenic immunoglobulin light chains by small molecules

Journal Article · Wed Apr 10 00:00:00 EDT 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1817567116· OSTI ID:1515308

^[1]; Yan, Nicholas L. ^[1]; Mortenson, David E. ^[1]; Rennella, Enrico ^[2]; Blundon, Joshua M. ^[1]; Gwin, Ryan M. ^[1]; Lin, Chung-Yon ^[1]; Stanfield, Robyn L. ^[1]; Brown, Steven J. ^[1]; Rosen, Hugh ^[1]; Spicer, Timothy P. ^[1]; Fernandez-Vega, Virneliz ^[1]; Merlini, Giampaolo ^[3]; Kay, Lewis E. ^[2]; Wilson, Ian A. ^[1]; Kelly, Jeffery W. ^[1]

The Scripps Research Inst., La Jolla, CA (United States)
Univ. of Toronto, ON (Canada)
Univ. of Pavia (Italy); Foundation Ist. di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, (Italy)

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. Specifically, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Canadian Institutes of Health Research (CIHR); George E. Hewitt Foundation for Medical Research; Lita Annenberg Hazen Foundation; National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Natural Sciences and Engineering Research Council of Canada (NSERC); Office of Research Infrastructure Programs (ORIP); Skaggs Institute for Chemical Biology; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1515308

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 17 Vol. 116; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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