ArticleBioorganic & medicinal chemistry letters2020
Structural basis for the stabilization of amyloidogenic immunoglobulin light chains by hydantoins.
Article in Bioorganic & medicinal chemistry letters, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 22 citations in OpenAlex.
- Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.Journal of molecular biology · 2026Article
- Small molecule stabilization of diverse amyloidogenic immunoglobulin light chains revealed by hydrogen-deuterium exchange mass spectrometry.bioRxiv : the preprint server for biology · 2026Article
- Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains.Journal of medicinal chemistry · 2024Article
- Review
- Conformational inhibitors of protein aggregation.Current opinion in structural biology · 2023Review
- Crystal Structures of Diaryl Hydrazone and Sulfone Stabilizers in Complex with an Amyloidogenic Light Chain Reveal an Alternate Ligand-Binding Cavity.Israel journal of chemistry · 2023Article
- Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis.Current opinion in chemical biology · 2023Review
- Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005.Nature communications · 2023Article
- Role of conformational dynamics in pathogenic protein aggregation.Current opinion in chemical biology · 2023Review
- A constant domain mutation in a patient-derived antibody light chain reveals principles of AL amyloidosis.Communications biology · 2023Article
- Amyloidogenic immunoglobulin light chain kinetic stabilizers comprising a simple urea linker module reveal a novel binding sub-site.Bioorganic & medicinal chemistry letters · 2022Article
- Article
- Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis.Molecules (Basel, Switzerland) · 2021Article
- Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.Journal of medicinal chemistry · 2021Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Misfolding and aggregation of immunoglobulin light chains (LCs) leads to the degeneration of post-mitotic tissue in the disease immunoglobulin LC amyloidosis (AL). We previously reported the discovery of small molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which slow or stop the LC aggregation cascade at the outset. A predominant structural category of kinetic stabilizers emerging from the high-throughput screen are coumarins substituted at the 7-position, which bind at the interface between the two variable domains of the light chain dimer. Here, we report the binding mode of another, more polar, LC kinetic stabilizer chemotype, 3,5-substituted hydantoins. Computational docking, solution nuclear magnetic resonance experiments, and x-ray crystallography show that the aromatic substructure emerging from the hydantoin 3-position occupies the same LC binding site as the coumarin ring. Notably, the hydantoin ring extends beyond the binding site mapped out by the coumarin hits. The hydantoin ring makes hydrogen bonds with both LC monomers simultaneously. The alkyl substructure at the hydantoin 5-position partially occupies a novel binding pocket proximal to the pocket occupied by the coumarin substructure. Overall, the hydantoin structural data suggest that a larger area of the LC variable-domain-variable-domain dimer interface is amenable to small molecule binding than previously demonstrated, which should facilitate development of more potent full-length LC kinetic stabilizers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.