Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity

Brandt, Sara J.; Mayer, John P.; Ford, James; Gelfanov, Vasily; DiMarchi, Richard D.

doi:10.1016/j.peptides.2017.11.022

Cited by 6 publications

(21 citation statements)

References 20 publications

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“…Previous phage display affinity screening identified peptides that can bind to the IR with sub-micromolar affinity 30 – 33 . Strikingly, while lacking sequence homology to insulin, these peptides induce robust IR auto-phosphorylation and potently activate IR signaling.…”

Section: Introductionmentioning

confidence: 99%

Activation of the insulin receptor by an insulin mimetic peptide

Park

Mayer

et al. 2022

Nat Commun

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Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin’s action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases.

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Section: Introductionmentioning

confidence: 99%

Activation of the insulin receptor by an insulin mimetic peptide

Park

Mayer

et al. 2022

Nat Commun

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“…4 A previous attempt has been made to develop a partial IR agonist with coincidental antagonistic activity by forming a disulfide bond between a linear S2 binding sequence from Ser-S661 and a chemical moiety affixed to LysB29 of insulin. 9 In this study, we use SrtAdirected ligation to fuse both linear S1 and S2 to the Cterminal A chain of Ins-AC and study the agonism and antagonism properties of these novel Ins-AC-based derivatives (Figure 2b). Moreover, since the first five amino acids of S2 have been proposed to play a key role in antagonism, 9 we synthesized a mutated Ins-AC-S2 (Ins-AC-S2-mut5) in which the first five amino acids, "SLEEE", were mutated to the linker, "SGSGS".…”

Section: Synthesis Of Insulin Derivatives With C-terminal a Chain Mod...mentioning

confidence: 99%

Antagonistic Insulin Derivative Suppresses Insulin-Induced Hypoglycemia

et al. 2023

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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.

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“…Interestingly, when the binding domain of the II (S961) peptide was chemically ligated to the Lys-29 position of the native insulin, the resulting conjugate III displayed partial agonism at the insulin receptor. 20 This compound retained near-full potency (EC50) compared to the native insulin but only ∼25% of maximal activity. The partial agonism of the conjugate was explained by a combination of the agonistic activity of the native insulin with the antagonistic activity of the appended peptidic moiety, which can occupy one of the binding sites on IR that are ordinarily cognate to the native insulin.…”

Section: ■ Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Discovery of Insulin Receptor Partial Agonists MK-5160 and MK-1092 as Novel Basal Insulins with Potential to Improve Therapeutic Index

et al. 2022

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We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20−70% of native insulin, and EC 50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.

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Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity

Cited by 6 publications

References 20 publications

Activation of the insulin receptor by an insulin mimetic peptide

Activation of the insulin receptor by an insulin mimetic peptide

Antagonistic Insulin Derivative Suppresses Insulin-Induced Hypoglycemia

Discovery of Insulin Receptor Partial Agonists MK-5160 and MK-1092 as Novel Basal Insulins with Potential to Improve Therapeutic Index

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