title: Engineering TGF-β superfamily ligands for clinical applications.
abstract: TGF-β superfamily ligands govern normal tissue development and homeostasis, and their dysfunction is a hallmark of many diseases. These ligands are also well defined both structurally and functionally. This review focuses on TGF-β superfamily ligand engineering for therapeutic purposes, in particular for regenerative medicine and musculoskeletal disorders. We describe the key discovery that structure-guided mutation of receptor-binding epitopes, especially swapping of these epitopes between ligands, results in new ligands with unique functional properties that can be harnessed clinically. Given the promising results with prototypical engineered TGF-β superfamily ligands, and the vast number of such molecules that remain to be produced and tested, this strategy is likely to hold great promise for the development of new biologics.
authors.affiliation: Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Drug Discovery Collaboratory, Joint Center for Biosciences, Incheon 406-840, Korea.
authors.forename: Witek
authors.initials: W
authors.lastname: Kwiatkowski
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gray
authors.affiliation: Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Drug Discovery Collaboratory, Joint Center for Biosciences, Incheon 406-840, Korea. Electronic address: choe@salk.edu.
authors.forename: Senyon
authors.initials: S
authors.lastname: Choe
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015202:Protein Engineering / Q000379:methods; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D016212:Transforming Growth Factor beta
keywords: BMP; TGF-β; activin; biologics; bone healing; cancer; cartilage healing; regenerative medicine