Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds

Huilin Yang, Umut Y. Ulge, Alfredo Quijano-Rubio, Zachary J. Bernstein, David R. Maestas, Jung Ho Chun, Wentao Wang, Jian Xin Lin, Kevin M. Jude, Srujan Singh, Brian T. Orcutt-Jahns, Peng Li, Jody Mou, Liam Chung, Yun Huai Kuo, Yasmin H. Ali, Aaron S. Meyer, Warren L. Grayson, Nicola M. Heller, K. Christopher GarciaWarren J. Leonard, Daniel Adriano Silva, Jennifer H. Elisseeff, David Baker, Jamie B. Spangler

Research output: Contribution to journalArticlepeer-review


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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)1127-1137
Number of pages11
JournalNature chemical biology
Issue number9
StatePublished - Sep 2023

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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