Structure‐function relationships of des‐(B26‐B30)‐insulin

Spoden, Martin; Gattner, Hans‐Gregor; Zahn, Helmut; Brandenburg, Dietrich

doi:10.1111/j.1399-3011.1995.tb00593.x

Cited by 8 publications

(3 citation statements)

References 23 publications

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“…Unexpectedly, alanine was found to be nearly equivalent to native hormone 142 while asparagine exhibited still higher activity. 157 Crystal structures of DPI and related analogs have been reported. 158,159 They demonstrate conservation of the structural elements central to receptor recognition, with one notable difference.…”

Section: Insulin Structure and Function 701mentioning

confidence: 98%

Insulin structure and function

2007

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Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported.

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Section: Insulin Structure and Function 701mentioning

confidence: 98%

Insulin structure and function

2007

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“…DTI-NH 2 was shown to have 110% binding affinity and 129% in vitro biological activity . Likewise, DPI-NH 2 , which is equipotent to insulin at binding (100−115%) ,,, , retained full in vivo hypoglycemic activity after intravenous injection into rats . These data and the results relating to analogues with specific substitutions at the B26 position do not support the hypothesis that residues B26−B30 are important for biological activity, and instead, we suggest that the observed discrepancy between binding affinity and biological activity of the shortened analogues could be caused by N-methylation of the B25−B26 peptide bond and specific substitutions at the B26 position.…”

Section: Discussionmentioning

confidence: 56%

Insulin Analogues with Modifications at Position B26. Divergence of Binding Affinity and Biological Activity

et al. 2008

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In this study, we prepared several shortened and full-length insulin analogues with substitutions at position B26. We compared the binding affinities of the analogues for rat adipose membranes with their ability to lower the plasma glucose level in nondiabetic Wistar rats in vivo after subcutaneous administration, and also with their ability to stimulate lipogenesis in vitro. We found that [NMeHisB26]-DTI-NH 2 and [NMeAlaB26]-DTI-NH 2 were very potent insulin analogues with respect to their binding affinities (214 and 465%, respectively, compared to that of human insulin), but they were significantly less potent than human insulin in vivo. Their full-length counterparts, [NMeHisB26]-insulin and [NMeAlaB26]-insulin, were less effective than human insulin with respect to binding affinity (10 and 21%, respectively) and in vivo activity, while [HisB26]-insulin exhibited properties similar to those of human insulin in all of the tests we carried out. The ability of selected analogues to stimulate lipogenesis in adipocytes was correlated with their biological potency in vivo. Taken together, our data suggest that the B26 residue and residues B26-B30 have ambiguous roles in binding affinity and in vivo activity. We hypothesize that our shortened analogues, [NMeHisB26]-DTI-NH 2 and [NMeAlaB26]-DTI-NH 2, have different modes of interaction with the insulin receptor compared with natural insulin and that these different modes of interaction result in a less effective metabolic response of the insulin receptor, despite the high binding potency of these analogues.

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“…Previous studies have shown that deleting the last five highly conserved residues at the C-terminus of the insulin B-chain still results in a molecule with significant potency. 77,78,91 In fact, changes in the new C-terminus (B25) of these truncated molecules, provide variants with increased potency at the IR compared to WT-Ins. 77,78,92 These insulins of different length and C-terminal modifications provided an ideal opportunity to explore the generalizability of MD/FEP as an in silico mutagenesis tool in peptide design.…”

Section: Discussionmentioning

confidence: 99%

Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor

Sena

Gromiha

Chatterji

et al. 2022

Preprint

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Insulin has been the cornerstone of diabetes treatment since its discovery over a century ago. Despite this, several aspects of insulin engagement with its target and off-target receptors remain unknown, thus limiting the use of structure-guided design of novel analogs. A recent spurt in structural information for the insulin and insulin-like growth factor 1 receptors (IR and IGF-1R), were leveraged in this study to gain a deeper, molecular-level understanding of ligand recognition at these targets. Molecular dynamics (MD) and free energy perturbation (FEP) were utilized to map the drivers of potency and specificity of several insulin variants including disease-linked mutations. The remarkable accuracy of MD-FEP in capturing functional trends (>80% of cases) across various insulin analogs underscored the method’s potential. The ability to deconvolute observations into receptor contributions, conformational perturbations and (or) solvent-network changes lays the foundations for its use in predictive design of future insulins and other therapeutic peptides.

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Structure‐function relationships of des‐(B26‐B30)‐insulin

Cited by 8 publications

References 23 publications

Insulin structure and function

Insulin structure and function

Insulin Analogues with Modifications at Position B26. Divergence of Binding Affinity and Biological Activity

Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor

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