Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain

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Abstract

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer.

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Boris Brumshtein

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Shannon R Esswein

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Lukasz Salwinski

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Martin L Phillips

Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Alan T Ly

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Duilio Cascio

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Michael R Sawaya

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
David S Eisenberg

Department of Biological Chemistry, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

For correspondence
david@mbi.ucla.edu

Competing interests
The authors declare that no competing interests exist.

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