Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis

Hemato

Jeffery W. Kelly¹  Joel N. Buxbaum²  Gareth J. Morgan³ 

[1] Department of Chemistry, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USA;Department of Molecular Medicine, The Scripps Research Institute, La Jolla, San Diego, CA 92037, USA;Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA;

关键词: light chain amyloidosis;    amyloid fibrils;    antibody light chains;    drug design;    kinetic stabilizer;    cardiomyopathy;   

DOI  :  10.3390/hemato2040042

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown