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The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure
Review

Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis

1
Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
2
The Amyloidosis Center, Boston University School of Medicine, Boston, MA 02118, USA
3
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USA
4
Department of Chemistry, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USA
5
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Giovanni Palladini
Received: 10 August 2021 / Revised: 28 September 2021 / Accepted: 30 September 2021 / Published: 5 October 2021
Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the natively folded state of full-length light chains could act as pharmacological kinetic stabilizers, protecting light chains against unfolding, proteolysis and aggregation. Although the sequence of the pathological light chain is unique to each patient, fortunately light chains have highly conserved residues that form binding sites for small molecule kinetic stabilizers. We envision that such stabilizers could complement existing and emerging therapies to benefit light chain amyloidosis patients. View Full-Text
Keywords: light chain amyloidosis; amyloid fibrils; antibody light chains; drug design; kinetic stabilizer; cardiomyopathy; pharmacological chaperone light chain amyloidosis; amyloid fibrils; antibody light chains; drug design; kinetic stabilizer; cardiomyopathy; pharmacological chaperone
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MDPI and ACS Style

Morgan, G.J.; Buxbaum, J.N.; Kelly, J.W. Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis. Hemato 2021, 2, 645-659. https://0-doi-org.brum.beds.ac.uk/10.3390/hemato2040042

AMA Style

Morgan GJ, Buxbaum JN, Kelly JW. Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis. Hemato. 2021; 2(4):645-659. https://0-doi-org.brum.beds.ac.uk/10.3390/hemato2040042

Chicago/Turabian Style

Morgan, Gareth J., Joel N. Buxbaum, and Jeffery W. Kelly 2021. "Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis" Hemato 2, no. 4: 645-659. https://0-doi-org.brum.beds.ac.uk/10.3390/hemato2040042

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