Soluble, prolonged-acting insulin derivatives. II. Degree of protraction and crystallizability of insulins substituted in positions A17, B8, B13, B27 and B30

Markussen, Jan; Diers, I.; Engesgaard, A.; Hansen, Mogens Trier; Hougaard, Philip; Langkjaer, L.; Norris, Kjeld; Ribel, Ulla; Sørensen, Annette; Sorensen, Elsie M. B.

doi:10.1093/protein/1.3.215

Cited by 71 publications

(36 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human insulin, insulin aspart, insulin lispro, insulin B10Asp, insulin A21Gly, and insulin detemir were produced by recombinant DNA techniques and purified essentially as previously described (13,14). Insulin glargine and insulin B31B32diArg were synthesized by enzymatic semisynthesis.…”

Section: Methodsmentioning

confidence: 99%

Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use.

et al. 2000

View full text Add to dashboard Cite

In recent years, analogs of human insulin have been engineered with the aim of improving therapy for people with diabetes. To ensure that the safety profile of the human hormone is not compromised by the molecular modifications, the toxico-pharmacological properties of insulin analogs should be carefully monitored. In this study, we compared the insulin and IGF-I receptor binding properties and metabolic and mitogenic potencies of insulin aspart (B28Asp human insulin), insulin lispro (B28Lys,B29Pro human insulin), insulin glargine (A21Gly,B31Arg,B32Arg human insulin), insulin detemir (NN304) [B29Lys(-tetradecanoyl),desB30 human insulin], and reference insulin analogs. Receptor affinities were measured using purified human receptors, insulin receptor dissociation rates were determined using Chinese hamster ovary cells overexpressing the human insulin receptor, metabolic potencies were evaluated using primary mouse adipocytes, and mitogenic potencies were determined in human osteosarcoma cells. Metabolic potencies correlated well with insulin receptor affinities. Mitogenic potencies in general correlated better with IGF-I receptor affinities than with insulin receptor off-rates. The 2 rapid-acting insulin analogs aspart and lispro resembled human insulin on all parameters, except for a slightly elevated IGF-I receptor affinity of lispro. In contrast, the 2 long-acting insulin analogs, glargine and detemir, differed significantly from human insulin. The combination of the B31B32diArg and A21Gly substitutions provided insulin glargine with a 6-to 8-fold increased IGF-I receptor affinity and mitogenic potency compared with human insulin. The attachment of a fatty acid chain to LysB29 provided insulin detemir with reduced receptor affinities and metabolic and mitogenic potencies but did not change the balance between mitogenic and metabolic potencies. The safety implications of the increased growth-stimulating potential of insulin glargine are unclear. The reduced in vitro potency of insulin detemir might explain why this analog is not as effective on a molar basis as human insulin in humans.

show abstract

Section: Methodsmentioning

confidence: 99%

Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use.

et al. 2000

View full text Add to dashboard Cite

show abstract

“…26 Indeed, the prototype analogues based on this principle were not developed clinically because of low bioavailability and variability of action. 27,28 Nevertheless, this principle was successfully used in later years to produce insulin glargine (Gly A21 Arg B31 Arg B32 human insulin), in which two arginine residues added to the C-terminus of the B-chain shift the isoelectric point from pH 5.4 to 6.7. 25,29 A second strategy aimed at producing an improved basal insulin was to engineer a stable hexamer by substituting the zinc ions situated in the core of the hexameric structure with cobalt ions.…”

Section: The Rationale For a Basal Insulin Analoguementioning

confidence: 99%

Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir

Kurtzhals

2004

Int J Obes

106

View full text Add to dashboard Cite

The suboptimal nature of the absorption profiles of human insulin formulations following subcutaneous administration has prompted the development of insulin analogues better suited for therapeutic use in diabetes mellitus. A particular challenge has been to engineer long-acting agents that do not produce unduly variable responses from one injection to another. One recent approach that has met with success has been to acylate, the insulin molecule with a fatty acid, thereby enabling reversible albumin binding. The first clinically available agent of this type is insulin detemir. Pharmacological studies have established that this principle is effective in prolonging action, primarily by retarding absorption. The solubility of insulin detemir in the vial and after injection and an important buffering mechanism effected by plasma albumin binding explain a significant decrease in within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. Owing to the extremely high ratio of albumin-binding sites to insulin detemir molecules at therapeutic concentrations, no safety considerations have been identified pertaining to albumin binding. The insulin detemir molecule retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Thus, insulin detemir offers the promise of an improved tolerability:efficacy ratio in the clinical setting.

show abstract

“…[1][2][3][4][5][6][7][8] Most recently, we speculated that it might be possible to retard the absorption of insulin from subcutaneous tissue and the distribution from the bloodstream to the insulin receptors by making the insulin molecule bind to human serum albumin (HSA). We obtained albumin binding insulins that retain 20-80% affinity for the insulin receptor by covalent attachment of long-chain fatty acids to the -amino group of Lys B29 .…”

Section: Introductionmentioning

confidence: 99%

Effect of Fatty Acids and Selected Drugs on the Albumin Binding of a Long-Acting, Acylated Insulin Analogue

Kurtzhals¹,

Havelund²,

Jonassen³

et al. 1997

Journal of Pharmaceutical Sciences

108

View full text Add to dashboard Cite

NN304 (LysB29-tetradecanoyl, des(B30)-insulin) is a new soluble, long-acting insulin analogue that is tightly bound to human serum albumin differentiating it from human insulin. In the present study, we investigate the effect of fatty acids and selected drugs on the binding of NN304 to human serum albumin in vitro. Binding of the first fatty acid equivalent to albumin does not affect the binding of NN304. None of the tested drugs compete with the binding of NN304 at drug-to-albumin concentration ratios of < 1. The binding of NN304 is shown to be independent of binding of drugs in the two major binding pockets that are located in domains IIA and IIIA of the albumin molecule. Tolbutamide and glibenclamide do not compete with NN304 for binding to albumin at therapeutic drug-to-albumin concentration ratios. High concentrations of acetylsalicylic acid and ibuprofen decrease the affinity of NN304 for albumin, but these interactions occur at drug-to-albumin concentration ratios that are higher than clinically relevant. In conclusion, NN304 is unlikely to be involved in clinically significant drug interactions at the albumin binding level. The unique ligand binding properties of serum albumin and its abundance in the extracellular fluids makes fatty acid acylation and albumin binding an attractive protraction principle for insulin and potentially also for other peptide drugs.

show abstract

Soluble, prolonged-acting insulin derivatives. II. Degree of protraction and crystallizability of insulins substituted in positions A17, B8, B13, B27 and B30

Cited by 71 publications

References 0 publications

Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use.

Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use.

Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir

Effect of Fatty Acids and Selected Drugs on the Albumin Binding of a Long-Acting, Acylated Insulin Analogue

Contact Info

Product

Resources

About