Protein-protein interactions: a structural view of inhibition strategies and the IL-23/IL-17 axis

Adv Protein Chem Struct Biol. 2020:121:253-303. doi: 10.1016/bs.apcsb.2019.12.006. Epub 2020 Jan 24.

Abstract

Protein-protein interactions are central to biology and provide opportunities to modulate disease with small-molecule or protein therapeutics. Recent developments in the understanding of the tractability of protein-protein interactions are discussed with a focus on the ligandable nature of protein-protein interaction surfaces. General principles of inhibiting protein-protein interactions are illustrated with structural biology examples from six members of the IL-23/IL-17 signaling family (IL-1, IL-6, IL-17, IL-23 RORγT and TNFα). These examples illustrate the different approaches to discover protein-protein interaction inhibitors on a target-specific basis that has proven fruitful in terms of discovering both small molecule and biologic based protein-protein interaction inhibitors.

Keywords: Biologics; IL-17; IL-23; Protein-protein interactions; Small molecules.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • Arthritis / drug therapy*
  • Arthritis / genetics
  • Arthritis / immunology
  • Arthritis / pathology
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Binding Sites / drug effects
  • Gene Expression Regulation
  • Humans
  • Immunologic Factors / chemistry
  • Immunologic Factors / therapeutic use*
  • Interleukin-17 / antagonists & inhibitors*
  • Interleukin-17 / chemistry
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-23 / antagonists & inhibitors*
  • Interleukin-23 / chemistry
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Models, Molecular
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / chemistry
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Secondary
  • Signal Transduction
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / therapeutic use
  • Tumor Necrosis Factor-alpha / chemistry
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antibodies, Monoclonal
  • IL17A protein, human
  • Immunologic Factors
  • Interleukin-17
  • Interleukin-23
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Small Molecule Libraries
  • Tumor Necrosis Factor-alpha