An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling

Selicharov&#225;, I; Kirk, NS; Kertisov&#225;, A; Lubos, M; Mitrov&#225;, K; Tich&#225;čkov&#225;, T; Ž&#225;kov&#225;, L; Chrudinov&#225;, M; Březinov&#225;, J; Harant, K; Voldřich, J; H&#225;jek, M; Huffman, DM; Jir&#225;ček, J

Author(s): Selicharová, I; Kirk, NS; Kertisová, A; Lubos, M; Mitrová, K; Ticháčková, T; Žáková, L; Chrudinová, M; Březinová, J; Harant, K; Voldřich, J; Hájek, M; Huffman, DM; Jiráček, J;
Details: Publication Year 2026-05-15,Volume 12,Issue #20,Page eaeb7558
Journal Title: Scientific Advances
Abstract: Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (1(Ins)), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. 1(Ins) binds IGF-1R ~1000-fold more strongly than native insulin, approaching IGF-1 levels. Cryo-electron microscopy structures reveal how minimal substitutions in 1(Ins) enable effective binding to both IR-A and IGF-1R. In neuronal cells, 1(Ins) robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, 1(Ins) regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets specific to 1(Ins). These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.
Publisher: AAAS
Keywords: Animals; *Insulin/pharmacology/chemistry/analogs & derivatives/metabolism; *Signal Transduction/drug effects; *Receptor, IGF Type 1/agonists/metabolism; Mice; Humans; Rats; *Receptor, Insulin/metabolism/agonists; *Protein Engineering; Protein Binding; Cryoelectron Microscopy; Neurons/metabolism/drug effects; Glucose/metabolism
Research Division(s): Structural Biology
PubMed ID: 42139356
Publisher's Version: https://doi.org/10.1126/sciadv.aeb7558
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.aeb7558
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-05-25 11:04:08

Last Modified: 2026-05-25 11:04:18