Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis
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....
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Hemato |
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| Online Access: | https://www.mdpi.com/2673-6357/2/4/42 |
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| author | Gareth J. Morgan Joel N. Buxbaum Jeffery W. Kelly |
| author_facet | Gareth J. Morgan Joel N. Buxbaum Jeffery W. Kelly |
| author_sort | Gareth J. Morgan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:00:43Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2673-6357 |
| language | English |
| last_indexed | 2024-03-10T04:00:43Z |
| publishDate | 2021-10-01 |
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| record_format | Article |
| series | Hemato |
| spelling | doaj.art-aea9c56e4bab45b592bded4784b3adcc2023-11-23T08:35:35ZengMDPI AGHemato2673-63572021-10-012464565910.3390/hemato2040042Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL AmyloidosisGareth J. Morgan0Joel N. Buxbaum1Jeffery W. Kelly2Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USADepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USADepartment of Chemistry, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USANon-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.https://www.mdpi.com/2673-6357/2/4/42light chain amyloidosisamyloid fibrilsantibody light chainsdrug designkinetic stabilizercardiomyopathy |
| spellingShingle | Gareth J. Morgan Joel N. Buxbaum Jeffery W. Kelly Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis Hemato light chain amyloidosis amyloid fibrils antibody light chains drug design kinetic stabilizer cardiomyopathy |
| title | Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis |
| title_full | Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis |
| title_fullStr | Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis |
| title_full_unstemmed | Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis |
| title_short | Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis |
| title_sort | light chain stabilization a therapeutic approach to ameliorate al amyloidosis |
| topic | light chain amyloidosis amyloid fibrils antibody light chains drug design kinetic stabilizer cardiomyopathy |
| url | https://www.mdpi.com/2673-6357/2/4/42 |
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