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A Screening Assay For Z α1‐Antitrypsin Aggregation
Author(s) -
LeMieux Monique Jenaie,
Rowe Erica,
Berthelier Valerie
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.907.6
Subject(s) - small molecule , protein aggregation , chemistry , secretion , cirrhosis , folding (dsp implementation) , drug discovery , protein folding , computational biology , microbiology and biotechnology , biochemistry , biology , medicine , electrical engineering , engineering , gastroenterology
It is well established that improper folding of proteins often leads to the formation of aggregates whose consequences are cellular impairment and cell death. Therefore, finding small molecules that can be used as therapeutic agents to prevent the aggregation process would revolutionize the treatment of numerous conformational diseases including α1‐antitrypsin deficiency. Aggregation of the mutant Z α1‐antitrypsin protein results in blocking of its secretion, consequently forming inclusion bodies and contributing, not only to the development of chronic obstructive pulmonary disease but also to hepatitis, cirrhosis and hepatocellular carcinoma. Critical molecular mechanisms of the aggregation process have been established and some crystallographic structures solved, however, no specific potent drug‐like small molecule “breakers” of aggregation have been identified. We have designed a 96‐well high‐throughput screening assay that can identify small molecules capable of inhibiting or slowing down Z α1‐antitrypsin aggregation.