Structural basis of IL-23 antagonism by an Alphabody protein scaffold
By J. Desmet, K. Verstraete, Y. Bloch, E. Lorent, Yurong Wen, B. Devreese, K. Vandenbroucke, S. Loverix, T. Hettmann, S. Deroo and 4 more. 2014
66 citations recorded by the source corpus.
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. Protein scaffolds can serve as alternatives to antibodies in a range of applications. Here, the authors report the design and development of Alphabody™, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold that the authors use to develop Alphabodies that can neutralize human IL-23 with high specificity and affinity.
Subfields: Immunology, Radiology, Nuclear Medicine and Imaging
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
- S. Detry
- S. Govindarajan
- S. Savvides
- I. Adamopoulos
- Y. Bloch
- L. Bouchareychas
- F. Haerynck
- R. Merceron
Citations in the corpus
- Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1 (2017, background): “This is an area that has been extensively developed over the last decade via antibody and non-antibody protein scaffolds alike (Desmet et al., 2014; Hawkes et al., 2017; Ramamurthy et al., 2012).”