Abstract:
:Protein scaffolds can provide a promising alternative to antibodies for various biomedical and biotechnological applications, including therapeutics. Here we describe the design and development of the Alphabody, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold. We report affinity-matured Alphabodies with favourable physicochemical properties that can specifically neutralize human interleukin (IL)-23, a pivotal therapeutic target in autoimmune inflammatory diseases such as psoriasis and multiple sclerosis. The crystal structure of human IL-23 in complex with an affinity-matured Alphabody reveals how the variable interhelical groove of the scaffold uniquely targets a large epitope on the p19 subunit of IL-23 to harness fully the hydrophobic and hydrogen-bonding potential of tryptophan and tyrosine residues contributed by p19 and the Alphabody, respectively. Thus, Alphabodies are suitable for targeting protein-protein interfaces of therapeutic importance and can be tailored to interrogate desired design and binding-mode principles via efficient selection and affinity-maturation strategies.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Desmet J,Verstraete K,Bloch Y,Lorent E,Wen Y,Devreese B,Vandenbroucke K,Loverix S,Hettmann T,Deroo S,Somers K,Henderikx P,Lasters I,Savvides SNdoi
10.1038/ncomms6237subject
Has Abstractpub_date
2014-10-30 00:00:00pages
5237issn
2041-1723pii
ncomms6237journal_volume
5pub_type
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