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Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds.
Yang, Huilin; Ulge, Umut Y; Quijano-Rubio, Alfredo; Bernstein, Zachary J; Maestas, David R; Chun, Jung-Ho; Wang, Wentao; Lin, Jian-Xin; Jude, Kevin M; Singh, Srujan; Orcutt-Jahns, Brian T; Li, Peng; Mou, Jody; Chung, Liam; Kuo, Yun-Huai; Ali, Yasmin H; Meyer, Aaron S; Grayson, Warren L; Heller, Nicola M; Garcia, K Christopher; Leonard, Warren J; Silva, Daniel-Adriano; Elisseeff, Jennifer H; Baker, David; Spangler, Jamie B.
Afiliación
  • Yang H; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Ulge UY; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Quijano-Rubio A; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Bernstein ZJ; Department of Bioengineering, University of Washington, Seattle, WA, USA.
  • Maestas DR; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Chun JH; Department of Bioengineering, University of Washington, Seattle, WA, USA.
  • Wang W; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Lin JX; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jude KM; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Singh S; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Orcutt-Jahns BT; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Li P; Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA.
  • Mou J; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Chung L; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Kuo YH; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ali YH; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • Meyer AS; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Grayson WL; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Heller NM; Department of Bioengineering, University of California, Los Angeles, CA, USA.
  • Garcia KC; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Leonard WJ; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Silva DA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Elisseeff JH; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Baker D; Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA.
  • Spangler JB; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
Nat Chem Biol ; 19(9): 1127-1137, 2023 09.
Article en En | MEDLINE | ID: mdl-37024727
ABSTRACT
The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Citocinas / Interleucina-4 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Citocinas / Interleucina-4 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos