Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 9, Pages 6273-6299Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00339
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Funding
- National Institutes of Health [DK046335, GM069832]
- F31 fellowship [HL154732]
- DOE Office of Science User Facility [DE-AC02-05CH11231, DE-AC0206CH11357]
- ALS-ENABLE program - National Institutes of Health, National Institute of General Medical Sciences [P30 GM124169-01]
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- NIH-Office of Research Infrastructure Programs, High-End Instrumentation Grant [1S10OD012289-01A1]
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The study identified drugs that could stabilize immunoglobulin light chains, suppressing protein aggregation through enhanced affinity. Analysis revealed potential stabilizers, which could improve the stability of the light chains, with some showing significant enhancement in affinity.
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 pi-pi 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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