ArticleProtein science : a publication of the Protein Society2013
Insulin analog with additional disulfide bond has increased stability and preserved activity.
Article in Protein science : a publication of the Protein Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 80 citations in OpenAlex.
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- Structural modulation of insulin by hydrophobic and hydrophilic molecules.RSC advances · 2023Article
- Supramolecular approaches for insulin stabilization without prolonged duration of action.Acta pharmaceutica Sinica. B · 2023Article
- Molecular Aspects of Insulin Aggregation and Various Therapeutic Interventions.ACS bio & med chem Au · 2022Review
- 'Smart' insulin-delivery technologies and intrinsic glucose-responsive insulin analogues.Diabetologia · 2021Review
- Heat-stability study of various insulin types in tropical temperature conditions: New insights towards improving diabetes care.PloS one · 2021Article
- Pharmacokinetic Analysis of Epithelial/Endothelial Cell Barriers in Microfluidic Bilayer Devices with an Air-Liquid Interface.Micromachines · 2020Article
- "Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.The Journal of biological chemistry · 2020Article
- Lysosomal protein thermal stability does not correlate with cellular half-life: global observations and a case study of tripeptidyl-peptidase 1.The Biochemical journal · 2020Article
- The Kinetics of Amyloid Fibril Formation byBiomolecules · 2020Article
- Novel four-disulfide insulin analog with high aggregation stability and potency.Chemical science · 2020Article
- Synthesis and Characterization of an A6-A11 Methylene Thioacetal Human Insulin Analogue with Enhanced Stability.Journal of medicinal chemistry · 2019Article
- Effects of localized interactions and surface properties on stability of protein-based therapeutics.The Journal of pharmacy and pharmacology · 2018Review
- Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding.The Journal of biological chemistry · 2018Article
- An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein.The Journal of biological chemistry · 2018Article
- Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices.Drug delivery and translational research · 2017Article
- Development of glucose-responsive 'smart' insulin systems.Current opinion in endocrinology, diabetes, and obesity · 2017Review
- Insulin Formulation Characterization-the Thioflavin T Assays.The AAPS journal · 2017Review
- In-Depth Characterization of Protein Disulfide Bonds by Online Liquid Chromatography-Electrochemistry-Mass Spectrometry.Journal of the American Society for Mass Spectrometry · 2016Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insulin is a key hormone controlling glucose homeostasis. All known vertebrate insulin analogs have a classical structure with three 100% conserved disulfide bonds that are essential for structural stability and thus the function of insulin. It might be hypothesized that an additional disulfide bond may enhance insulin structural stability which would be highly desirable in a pharmaceutical use. To address this hypothesis, we designed insulin with an additional interchain disulfide bond in positions A10/B4 based on Cα-Cα distances, solvent exposure, and side-chain orientation in human insulin (HI) structure. This insulin analog had increased affinity for the insulin receptor and apparently augmented glucodynamic potency in a normal rat model compared with HI. Addition of the disulfide bond also resulted in a 34.6°C increase in melting temperature and prevented insulin fibril formation under high physical stress even though the C-terminus of the B-chain thought to be directly involved in fibril formation was not modified. Importantly, this analog was capable of forming hexamer upon Zn addition as typical for wild-type insulin and its crystal structure showed only minor deviations from the classical insulin structure. Furthermore, the additional disulfide bond prevented this insulin analog from adopting the R-state conformation and thus showing that the R-state conformation is not a prerequisite for binding to insulin receptor as previously suggested. In summary, this is the first example of an insulin analog featuring a fourth disulfide bond with increased structural stability and retained function.
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