Structural basis of IL-23 antagonism by an Alphabody protein scaffold

Johan Desmet (), Kenneth Verstraete, Yehudi Bloch, Eric Lorent, Yurong Wen, Bart Devreese, Karen Vandenbroucke, Stefan Loverix, Thore Hettmann, Sabrina Deroo, Klaartje Somers, Paula Henderikx, Ignace Lasters and Savvas N. Savvides ()
Additional contact information
Johan Desmet: COMPLIX N.V.
Kenneth Verstraete: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University
Yehudi Bloch: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University
Eric Lorent: COMPLIX N.V.
Yurong Wen: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University
Bart Devreese: Unit for Biological Mass spectrometry and Proteomics, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University
Karen Vandenbroucke: COMPLIX N.V.
Stefan Loverix: COMPLIX N.V.
Thore Hettmann: COMPLIX N.V.
Sabrina Deroo: COMPLIX N.V.
Klaartje Somers: COMPLIX N.V.
Paula Henderikx: COMPLIX N.V.
Ignace Lasters: COMPLIX N.V.
Savvas N. Savvides: Unit for Structural Biology, Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE), Ghent University

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6237

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