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

<div class='caption-title'>Schematic overview of the Alphabody platform.</div>
<div class='caption-title'>Stability and folding of the Alphabody scaffold.</div>
<div class='caption-title'>Binding properties of affinity-matured Alphabodies against human IL-23.</div>
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 SN
OpenAccess logo Nat Commun 5 5237 (2014)
Cited: 32 times
EuropePMC logo PMID: 25354530

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.

Articles - 5mj3 mentioned but not cited (5)

  1. Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1. Bloch Y, Bouchareychas L, Merceron R, Składanowska K, Van den Bossche L, Detry S, Govindarajan S, Elewaut D, Haerynck F, Dullaers M, Adamopoulos IE, Savvides SN. Immunity 48 45-58.e6 (2018)
  2. The molecular basis of chaperone-mediated interleukin 23 assembly control. Meier S, Bohnacker S, Klose CJ, Lopez A, Choe CA, Schmid PWN, Bloemeke N, Rührnößl F, Haslbeck M, Bieren JE, Sattler M, Huang PS, Feige MJ. Nat Commun 10 4121 (2019)
  3. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. Pannecoucke E, Van Trimpont M, Desmet J, Pieters T, Reunes L, Demoen L, Vuylsteke M, Loverix S, Vandenbroucke K, Alard P, Henderikx P, Deroo S, Baatz F, Lorent E, Thiolloy S, Somers K, McGrath Y, Van Vlierberghe P, Lasters I, Savvides SN. Sci Adv 7 eabe1682 (2021)
  4. Homogeneously N-glycosylated proteins derived from the GlycoDelete HEK293 cell line enable diffraction-quality crystallogenesis. Kozak S, Bloch Y, De Munck S, Mikula A, Bento I, Savvides SN, Meijers R. Acta Crystallogr D Struct Biol 76 1244-1255 (2020)
  5. Network Pharmacology and Bioinformatics Analysis Identifies Potential Therapeutic Targets of Paxlovid Against LUAD/COVID-19. Zhang W, Yang Z, Zhou F, Wei Y, Ma X. Front Endocrinol (Lausanne) 13 935906 (2022)


Reviews citing this publication (13)

  1. Cytokines in psoriasis. Baliwag J, Barnes DH, Johnston A. Cytokine 73 342-350 (2015)
  2. Non-immunoglobulin scaffolds: a focus on their targets. Škrlec K, Štrukelj B, Berlec A. Trends Biotechnol 33 408-418 (2015)
  3. Direct-acting antivirals and host-targeting strategies to combat enterovirus infections. Bauer L, Lyoo H, van der Schaar HM, Strating JR, van Kuppeveld FJ. Curr Opin Virol 24 1-8 (2017)
  4. Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis. Yu X, Yang YP, Dikici E, Deo SK, Daunert S. Annu Rev Anal Chem (Palo Alto Calif) 10 293-320 (2017)
  5. Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Felix J, Savvides SN. Nat Rev Immunol 17 112-129 (2017)
  6. The IL-12 Cytokine and Receptor Family in Graft-vs.-Host Disease. Bastian D, Wu Y, Betts BC, Yu XZ. Front Immunol 10 988 (2019)
  7. Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities. Pastor-Fernández G, Mariblanca IR, Navarro MN. Cells 9 E2044 (2020)
  8. Bioconjugation - using selective chemistry to enhance the properties of proteins and peptides as therapeutics and carriers. Gunnoo SB, Madder A. Org Biomol Chem 14 8002-8013 (2016)
  9. IL-12 and IL-23-Close Relatives with Structural Homologies but Distinct Immunological Functions. Floss DM, Moll JM, Scheller J. Cells 9 E2184 (2020)
  10. Polyproteins in structural biology. Crépin T, Swale C, Monod A, Garzoni F, Chaillet M, Berger I. Curr Opin Struct Biol 32 139-146 (2015)
  11. Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight. Nguyen CT, Bloch Y, Składanowska K, Savvides SN, Adamopoulos IE. Clin Immunol 206 15-22 (2019)
  12. Understanding a protein fold: The physics, chemistry, and biology of α-helical coiled coils. Woolfson DN. J Biol Chem 299 104579 (2023)
  13. The Role of IL-23 Inhibitors in Crohn's Disease. Fanizza J, D'Amico F, Lusetti F, Fasulo E, Allocca M, Furfaro F, Zilli A, Parigi TL, Radice S, Peyrin-Biroulet L, Danese S, Fiorino G. J Clin Med 13 224 (2023)

Articles citing this publication (14)



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