Interleukin-2 superkines by computational design.

Autor:	Ren J; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; HHMI, Stanford University School of Medicine, Stanford, CA 94305., Chu AE; Department of Bioengineering, Stanford University, Stanford, CA 94305.; Biophysics Program, Stanford University, Stanford, CA 94305., Jude KM; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; HHMI, Stanford University School of Medicine, Stanford, CA 94305., Picton LK; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; HHMI, Stanford University School of Medicine, Stanford, CA 94305., Kare AJ; Department of Bioengineering, Stanford University, Stanford, CA 94305., Su L; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; HHMI, Stanford University School of Medicine, Stanford, CA 94305., Montano Romero A; Department of Bioengineering, Stanford University, Stanford, CA 94305., Huang PS; Department of Bioengineering, Stanford University, Stanford, CA 94305.; Biophysics Program, Stanford University, Stanford, CA 94305., Garcia KC; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.; HHMI, Stanford University School of Medicine, Stanford, CA 94305.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Mar 22; Vol. 119 (12), pp. e2117401119. Date of Electronic Publication: 2022 Mar 16.
DOI:	10.1073/pnas.2117401119
Abstrakt:	Affinity maturation of protein–protein interactions is an important approach in the development of therapeutic proteins such as cytokines. Typical experimental strategies involve targeting the cytokine-receptor interface with combinatorial libraries and then selecting for higher-affinity variants. Mutations to the binding scaffold are usually not considered main drivers for improved affinity. Here we demonstrate that computational design can provide affinity-enhanced variants of interleukin-2 (IL-2) “out of the box” without any requirement for interface engineering. Using a strategy of global IL-2 structural stabilization targeting metastable regions of the three-dimensional structure, rather than the receptor binding interfaces, we computationally designed thermostable IL-2 variants with up to 40-fold higher affinity for IL-2Rβ without any library-based optimization. These IL-2 analogs exhibited CD25-independent activities on T and natural killer (NK) cells both in vitro and in vivo, mimicking the properties of the IL-2 superkine “super-2” that was engineered through yeast surface display [A. M. Levin et al., Nature, 484, 529–533 (2012)]. Structure-guided stabilization of cytokines is a powerful approach to affinity maturation with applications to many cytokine and protein–protein interactions.
Databáze:	MEDLINE
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