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Publication Abstract from PubMed

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-2Rbeta 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.

Interleukin-2 superkines by computational design.,Ren J, Chu AE, Jude KM, Picton LK, Kare AJ, Su L, Montano Romero A, Huang PS, Garcia KC Proc Natl Acad Sci U S A. 2022 Mar 22;119(12):e2117401119. doi: , 10.1073/pnas.2117401119. Epub 2022 Mar 16. PMID:35294290^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.