Antagonistic Insulin Derivative Suppresses Insulin-Induced Hypoglycemia.
Journal of medicinal chemistry
Insulin derivatives provide new functions that are distinctive from native insulin. We investigated insulin modifications on the C-terminal A chain with insulin receptor (IR) peptide binders and presented a full and potent IR antagonist. We prepared insulin precursors featuring a sortase A (SrtA) recognition sequence, LPETGG, at the C-terminal A chain and used a SrtA-mediated ligation method to synthesize insulin derivatives. The insulin precursor exhibits full IR agonism potency, similar to native human insulin. We explored derivatives with linear IR binding peptides attached to the insulin C-terminal A chain. One insulin derivative with an IR binder (Ins-AC-S2) can fully antagonize IR activation by insulin, as confirmed by cell-based assays. This IR antagonist suppresses insulin-induced hypoglycemia in a streptozotocin-induced diabetic rat model. This study provides a new direction toward insulin antagonist development.
View details for DOI 10.1021/acs.jmedchem.3c00280
View details for PubMedID 37227951
Modifying insulin to improve performance.
Science (New York, N.Y.)
2022; 376 (6599): 1270-1271
A platform to enable precise modifications of insulin could improve drug functionality.
View details for DOI 10.1126/science.abq7217
View details for PubMedID 35709283
Synthesis and Characterization of Phenylboronic Acid-Modified Insulin With Glucose-Dependent Solubility.
Frontiers in chemistry
2022; 10: 859133
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
2021; 11 (9): 2719-2725
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
2021; 218 (3)
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