Yuankun Dao

All Publications

• Monomeric Insulin Analog and Stabilizing Excipient Enabled Ultrafast Insulin Formulation. Advanced materials (Deerfield Beach, Fla.) Zhang, Y., Lin, T., Tran, N. L., Jung, J., Blakely, A., Dao, Y., Austin, M. J., Lal, R. A., Hill, C. P., Chou, D. H. 2026: e73767

  Abstract

  The speed of insulin therapy remains fundamentally constrained by the self-association of insulin into hexamers. Here, a materials-based strategy is introduced to stabilize HALQ, a monomeric insulin analog, using a non-interacting inulin-derived excipient (BN-Inu). BN-Inu markedly mitigates aggregation and maintains HALQ stability for 96 h under stress and for at least 30 days at room temperature. In a porcine model of diabetes, monomeric HALQ exhibits significantly accelerated absorption and a shorter duration of action than the ultrarapid insulin aspart Fiasp. This "fast-on, fast-off" profile is consistent with faster clearance from the subcutaneous depot, more closely synchronizes with endogenous prandial insulin physiology. Addition of clinically used absorption enhancers further accelerates its pharmacokinetic profile, producing a faster time-to-peak and reduced exposure relative to ultrarapid insulin lispro Lyumjev in this animal model. Furthermore, translation to human physiology was evaluated through pharmacokinetic modeling, which predicts that HALQ could reduce time-to-peak from 60 to 39 min and shorten duration of action from 143 to 84 min in humans. These simulations suggest the potential utility of achieving a step-change in the speed of insulin therapy. These findings demonstrate that monomer-stabilizing excipients enable next-generation ultrafast insulin formulations with the potential to improve glycemic control in diabetes.

  View details for DOI 10.1002/adma.73767

  View details for PubMedID 42436611

• Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2. Nature communications Vogel, A., Blakely, A., Dao, Y., Lin, N., Chou, D., Hill, C. P. 2026; 17 (1)

  Abstract

  Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of alphaCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.

  View details for DOI 10.1038/s41467-026-73851-1

  View details for PubMedID 42265100

• Synthesis of Insulin-desB30 Analogs via an Enzymatically Removable N-Terminal Solubilizing Tag. Organic letters Dao, Y., Lin, T., Le Bich Tran, N., Griffiths Chen, F., Hung-Chieh Chou, D. 2025

  Abstract

  Chemical synthesis enables rapid access to designed insulin analogs, but the efficiency is hindered by the insulin A-chain's poor solubility. We report a streamlined route using direct Fmoc-SPPS of a native A chain aided by a temporary polylysine solubility tag removable by Lys-C under mild aqueous conditions. The workflow improves isolation, folding, and chain combination and generalizes to difficult targets (A16Pro mutant insulin, methyl-ketone A6-A11 surrogate, four-disulfide insulin), delivering high-purity products.

  View details for DOI 10.1021/acs.orglett.5c04131

  View details for PubMedID 41229176

• Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands. bioRxiv : the preprint server for biology Vogel, A., Blakely, A., Dao, Y., Lin, N. P., Chou, D., Hill, C. P. 2025

  Abstract

  Congenital hyperinsulinism (HI) is a rare genetic disease characterized by overproduction of insulin. One class of potential HI treatments is insulin receptor (IR) antagonists like S961 and Ins-AC-S2, peptides composed of binding segments for each of the IR sites capable of binding insulin: site 1 and site 2. Notably, S597 - containing the same IR binding segments as S961 but in the opposite order (site 2-site 1) - is an IR agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of IR, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is dictated by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we uncover subtle differences between the binding mechanisms of S961 and Ins-AC-S2 to IR, which include displacement or engagement of αCT, respectively, and a novel binding interface between the Ins-AC-S2 insulin and the receptor. These structural insights may inform development of next generation IR antagonists for treatment of HI.

  View details for DOI 10.1101/2025.08.23.671589

  View details for PubMedID 40894704

  View details for PubMedCentralID PMC12393571

• Modulation of insulin receptor activation through controlled folding of peptide ligands. Organic & biomolecular chemistry Li, W., Dao, Y., Lin, T., Austin, M. J., Lin, N. P., Chou, D. H. 2025

  Abstract

  Insulin receptor (IR) activation requires coordinated engagement of two distinct insulin-binding sites, and recent structural insights have highlighted the role of a disulfide bond in IR agonist S597 in the S597-IR complex. In this study, we synthesized and evaluated analogs of S597 and the IR antagonist Ins-AC-S2, replacing their native disulfide bridges with alternative linkages. While these modifications had minimal impact on Ins-AC-S2's antagonistic activity, they significantly reduced the agonistic potency of S597, suggesting that conformational stability is critical for receptor activation. Our findings provide a structural basis for designing non-insulin ligands to selectively activate or inhibit the insulin receptor, with potential therapeutic implications.

  View details for DOI 10.1039/d5ob00363f

  View details for PubMedID 40277138