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Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.

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Τίτλος: Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.
Συγγραφείς: Peterle D; Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA. Electronic address: daniele@peptone.io., Yan NL; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Klimtchuk ES; Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Srinivasu BY; Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA., Brusic V; Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Rhoades D; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Wales TE; Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA., Gursky O; Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Kelly JW; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Engen JR; Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA., Morgan GJ; Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Section of Hematology and Medical Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. Electronic address: gjmorgan@bu.edu.
Πηγή: Journal of molecular biology [J Mol Biol] 2026 Oct 01; Vol. 438 (19), pp. 169917. Date of Electronic Publication: 2026 Jun 29.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 2985088R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1089-8638 (Electronic) Linking ISSN: 00222836 NLM ISO Abbreviation: J Mol Biol Subsets: MEDLINE
Imprint Name(s): Publication: Amsterdam : Elsevier
Original Publication: 1959- : London : Academic Press
Ιατρικοί όροι (MeSH): Immunoglobulin Light Chains*/chemistry , Immunoglobulin Light Chains*/metabolism , Hydrogen Deuterium Exchange-Mass Spectrometry*/methods , Amyloid*/chemistry , Amyloid*/metabolism , Amyloidogenic Proteins*/chemistry , Amyloidogenic Proteins*/metabolism, Immunoglobulin Light-chain Amyloidosis/metabolism ; Humans ; Deuterium Exchange Measurement ; Protein Stability ; Protein Binding ; Protein Conformation ; Mass Spectrometry ; Proteolysis
Περίληψη: Immunoglobulin light chains, a component of antibodies, can misfold and aggregate to cause systemic AL amyloidosis. Aggregation, including amyloid fibril formation, requires unfolding of the full-length light chain from its native state, and in most cases aberrant proteolysis. Small molecules that bind to the native state of light chains to stabilize them against conformational excursions and proteolysis are under development as drug candidates for AL amyloidosis. Since each patient has a unique light chain sequence, a challenge for candidate stabilizer drugs is to bind multiple light chains and suppress their dynamics. Here, we used hydrogen-deuterium exchange coupled to mass spectrometry to characterize the binding of small molecule stabilizers to λ light chain proteins. We measured the effects of six small molecules on a previously studied light chain, then characterized a further six amyloidogenic light chains in the presence and absence of the most efficacious stabilizer. Despite structural and dynamic differences among the light chains, stabilizer binding led to decreased hydrogen exchange rates, consistent with reduced local and global unfolding. Protection upon binding was most prominent in residues within complementarity determining region 3 and framework region 4 of the light chain variable domains, which undergo major conformational changes enabling amyloid formation. Stabilizer binding reduced the rate at which all light chains were cleaved by protease, and delayed amyloid formation in vitro. These data show that these stabilizers suppress the range of conformational dynamics associated with light chain aggregation, supporting their therapeutic potential.
(Copyright © 2026 Elsevier Ltd. All rights reserved.)
Competing Interests: Declaration of competing interest NLY, GJM and JWK are authors on a patent that describes the use of kinetic stabilizers as a potential therapy for AL amyloidosis. JWK is a founder and board member of Protego Biopharma.
Σχόλια: Update of: bioRxiv. 2026 Jan 08:2026.01.07.698275. doi: 10.64898/2026.01.07.698275.. (PMID: 41542593)
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Grant Information: R01 GM067260 United States GM NIGMS NIH HHS; R01 GM135158 United States GM NIGMS NIH HHS; R01 HL157566 United States HL NHLBI NIH HHS
Contributed Indexing: Keywords: HDX-MS; amyloid fibrils; immunoglobulin light chain amyloidosis; light chain kinetic stabilizers; protein stability and dynamics
Substance Nomenclature: 0 (Immunoglobulin Light Chains)
0 (Amyloid)
0 (Amyloidogenic Proteins)
Entry Date(s): Date Created: 20260629 Date Completed: 20260806 Latest Revision: 20260816
Update Code: 20260816
PubMed Central ID: PMC13477207
DOI: 10.1016/j.jmb.2026.169917
PMID: 42372939
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1089-8638
DOI:10.1016/j.jmb.2026.169917