Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
13 05 2021
13 05 2021
Historique:
pubmed:
4
5
2021
medline:
16
6
2021
entrez:
3
5
2021
Statut:
ppublish
Résumé
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 EC
Identifiants
pubmed: 33939422
doi: 10.1021/acs.jmedchem.1c00339
pmc: PMC8428256
mid: NIHMS1737809
doi:
Substances chimiques
Amyloid
0
Coumarins
0
Immunoglobulin Light Chains
0
coumarin
A4VZ22K1WT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
6273-6299Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL157566
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124169
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK046335
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM069832
Pays : United States
Organisme : NIH HHS
ID : S10 OD012289
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK046335
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL154732
Pays : United States
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