{"doi":"10.1073/pnas.2117401119","title":"Interleukin-2 superkines by computational design","abstract":"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.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":247408,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":701180,"name":"Alexander E. Chu","orcid":"0000-0002-6219-7887","position":1,"is_corresponding":false},{"id":260360,"name":"Kevin M. Jude","orcid":"0000-0002-3675-5136","position":2,"is_corresponding":false},{"id":625479,"name":"Lora K. Picton","orcid":"0000-0002-0482-5187","position":3,"is_corresponding":false},{"id":286465,"name":"Aris J. Kare","orcid":"0000-0002-4896-2853","position":4,"is_corresponding":false},{"id":625421,"name":"Leon Su","orcid":"0000-0001-7654-9997","position":5,"is_corresponding":false},{"id":885425,"name":"Alejandra Montaño Romero","orcid":null,"position":6,"is_corresponding":false},{"id":317333,"name":"Po‐Ssu Huang","orcid":"0000-0002-7948-2895","position":7,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":8,"is_corresponding":false},{"id":884970,"name":"Junming Ren","orcid":"0000-0002-0764-0882","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T00:23:53.369530Z","pmid":"35294290","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}