TY - JOUR
T1 - Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds
AU - Yang, Huilin
AU - Ulge, Umut Y.
AU - Quijano-Rubio, Alfredo
AU - Bernstein, Zachary J.
AU - Maestas, David R.
AU - Chun, Jung Ho
AU - Wang, Wentao
AU - Lin, Jian Xin
AU - Jude, Kevin M.
AU - Singh, Srujan
AU - Orcutt-Jahns, Brian T.
AU - Li, Peng
AU - Mou, Jody
AU - Chung, Liam
AU - Kuo, Yun Huai
AU - Ali, Yasmin H.
AU - Meyer, Aaron S.
AU - Grayson, Warren L.
AU - Heller, Nicola M.
AU - Garcia, K. Christopher
AU - Leonard, Warren J.
AU - Silva, Daniel Adriano
AU - Elisseeff, Jennifer H.
AU - Baker, David
AU - Spangler, Jamie B.
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/9
Y1 - 2023/9
N2 - 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.]
AB - 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.]
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U2 - 10.1038/s41589-023-01313-6
DO - 10.1038/s41589-023-01313-6
M3 - Article
C2 - 37024727
AN - SCOPUS:85152065543
SN - 1552-4450
VL - 19
SP - 1127
EP - 1137
JO - Nature chemical biology
JF - Nature chemical biology
IS - 9
ER -