title: Identification of aggregation inhibitors of the human antibody light chain repertoire by phage display.
abstract: Protein aggregation hinders the development of biologics and underpins the molecular basis of many human diseases. Considerable variation of aggregation propensity exists not only between different proteins, but also within a single homologous family, which complicates analyses. A classic example is observed among human antibody light chains, which aggregate in a clonally specific manner, driven by sequence diversity within their variable domains. Here, we utilise a library versus library strategy, based on phage display and a chemical library of FDA approved drugs, to overcome this limitation. Our approach allowed the identification of small molecule drugs that inhibit the aggregation of the human light chain repertoire. It also provides a general template for the small molecule targeting of diverse protein families.
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia The University of New South Wales, Faculty of Medicine, St Vincent's Clinical School, Darlinghurst, Sydney, NSW 2010, Australia.
authors: Joseph
authors: J
authors: Swift
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia The University of New South Wales, Faculty of Medicine, St Vincent's Clinical School, Darlinghurst, Sydney, NSW 2010, Australia.
authors: Sopany
authors: S
authors: Saing
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors: Romain
authors: R
authors: Rouet
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors: Kip
authors: K
authors: Dudgeon
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors: Peter
authors: P
authors: Schofield
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia The University of New South Wales, Faculty of Medicine, St Vincent's Clinical School, Darlinghurst, Sydney, NSW 2010, Australia.
authors: William
authors: W
authors: Sewell
authors: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia The University of New South Wales, Faculty of Medicine, St Vincent's Clinical School, Darlinghurst, Sydney, NSW 2010, Australia d.christ@garvan.org.au.
authors: Daniel
authors: D
authors: Christ
mesh_terms: D061505:Cell Surface Display Techniques / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects*
chemical_list: D007147:Immunoglobulin Light Chains; D066329:Protein Aggregates
keywords: antibodies; human antibody variable domains; light chain; phage display; protein aggregation