All Publications


  • Synthesis and Characterization of Phenylboronic Acid-Modified Insulin With Glucose-Dependent Solubility. Frontiers in chemistry Lin, N., Zheng, N., Purushottam, L., Zhang, Y. W., Chou, D. H. 2022; 10: 859133

    Abstract

    Glucose-responsive insulin represents a promising approach to regulate blood glucose levels. We previously showed that attaching two fluorophenylboronic acid (FPBA) residues to the C-terminal B chain of insulin glargine led to glucose-dependent solubility. Herein, we demonstrated that relocating FPBA from B chain to A chain increased the baseline solubility without affecting its potency. Furthermore, increasing the number of FPBA groups led to increased glucose-dependent solubility.

    View details for DOI 10.3389/fchem.2022.859133

    View details for PubMedID 35372263

  • Facile synthesis of insulin fusion derivatives through sortase A ligation. Acta pharmaceutica Sinica. B Disotuar, M. M., Smith, J. A., Li, J., Alam, S., Lin, N., Chou, D. H. 2021; 11 (9): 2719-2725

    Abstract

    Insulin derivatives such as insulin detemir and insulin degludec are U.S. Food and Drug Administration (FDA)-approved long-acting insulin currently used by millions of people with diabetes. These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity. New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin. Herein, we report a new method using sortase A (SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain. This new insulin molecule (Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives. We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and invivo bioactivity. This enzymatic method can therefore be used for future insulin design and development.

    View details for DOI 10.1016/j.apsb.2020.11.011

    View details for PubMedID 34589392

  • Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes. The Journal of experimental medicine Kim, H., Perovanovic, J., Shakya, A., Shen, Z., German, C. N., Ibarra, A., Jafek, J. L., Lin, N., Evavold, B. D., Chou, D. H., Jensen, P. E., He, X., Tantin, D. 2021; 218 (3)

    Abstract

    The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.

    View details for DOI 10.1084/jem.20200533

    View details for PubMedID 33295943