Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design
- Nicholas L. YanNicholas L. YanDepartment of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Nicholas L. Yan
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- Diogo Santos-MartinsDiogo Santos-MartinsDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Diogo Santos-Martins
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- Reji NairReji NairDepartment of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Reji Nair
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- Alan ChuAlan ChuCalifornia Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, United StatesMore by Alan Chu
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- Ian A. WilsonIan A. WilsonDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Ian A. Wilson
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- Kristen A. JohnsonKristen A. JohnsonCalifornia Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, United StatesMore by Kristen A. Johnson
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- Stefano ForliStefano ForliDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Stefano Forli
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- Gareth J. MorganGareth J. MorganSection of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, United StatesThe Amyloidosis Center, Boston University School of Medicine, Boston, Massachusetts 02118, United StatesMore by Gareth J. Morgan
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- H. Michael Petrassi*H. Michael Petrassi*Email: [email protected]California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, United StatesMore by H. Michael Petrassi
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- Jeffery W. Kelly*Jeffery W. Kelly*Email: [email protected]Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United StatesThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Jeffery W. Kelly
Abstract
In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC50 values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π–π stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.
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(1)
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(2)
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- Ramona M. Absmeier, Georg J. Rottenaicher, Hristo L. Svilenov, Pamina Kazman, Johannes Buchner. Antibodies gone bad – the molecular mechanism of light chain amyloidosis. The FEBS Journal 2023, 290
(6)
, 1398-1419. https://doi.org/10.1111/febs.16390
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(1)
, 260. https://doi.org/10.3390/molecules28010260
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(22)
https://doi.org/10.1002/ejoc.202200336
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(19)
, 2918-2930. https://doi.org/10.1182/blood.2020008737
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(1)
, 47-62. https://doi.org/10.3390/hemato3010005
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(1)
, 24-29. https://doi.org/10.1002/adsc.202100940
- Gareth J. Morgan, Joel N. Buxbaum, Jeffery W. Kelly. Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis. Hemato 2021, 2
(4)
, 645-659. https://doi.org/10.3390/hemato2040042
- Gareth J. Morgan. Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis. Molecules 2021, 26
(12)
, 3571. https://doi.org/10.3390/molecules26123571