Exploring the Implications of Vitamin B₁₂ Conjugation to Insulin on Insulin Receptor Binding

Abstract

We recently reported a vitamin B(12) (B(12)) based insulin conjugate that produced significantly decreased blood glucose levels in diabetic STZ-rat models. The results of this study posed a fundamental question, namely what implications does B(12) conjugation have on insulin's interaction with the insulin receptor (IR)? To explore this question we used a combination of molecular dynamics simulations and immunoelectron microscopy, and the results are described herein. This investigation demonstrates that chemical modification of insulin by linking relatively large pendant groups does not inherently interfere with IR recognition. Furthermore, given that we have previously demonstrated a significant drop in blood glucose concentration following the oral administration of the B(12)-insulin bioconjugate used in this work, it is reasonable to conclude that the IR recognition described herein is associated with maintenance of biological activity for insulin. This outcome offers significant research scope for chemical modification of insulin with the purpose of improving oral-uptake efficiency.

Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

“…The B 12 transport system of mammals has been implicated in the delivery of various small‐molecule drugs and peptides through the corresponding B 12 conjugates (see, e.g., refs. , , , , and ). However, details of the interaction between modified Cbls and the major human Cbl transporters have barely been explored, with just a few studies devoted to this subject .…”

Recent trends in the development of vitamin B12derivatives for medicinal applications

“…15,40,50,115,116 This strategy takes advantage of the highly sophisticated dietary uptake mechanism of B 12 , but requires modification of the basic structure of the natural product. 116,117 Indeed, points of structural modifications of native B 12 have to be chosen meticulously, in order to interfere the least with the binding pockets of the proteins and thus keep the biochemical uptake pathways intact. 116,117 Indeed, points of structural modifications of native B 12 have to be chosen meticulously, in order to interfere the least with the binding pockets of the proteins and thus keep the biochemical uptake pathways intact.…”

“…However, cellular uptake was subsequently shown for another vitamin B 12 -CORM derivative, using synchrotron FTIR spectromicroscopy measurements. 117,144,146,147,165 This concept has been mainly pioneered by the groups of Grissom, Fedosov and Doyle. This compound was -as expected -inactive in the dark, but showed light-activated protection of fibroblasts from death under conditions of hypoxia and metabolic depletion.…”

Facilitating the Cellular Accumulation of Pt-Based Chemotherapeutic Drugs

“…Furthermore, B12 not only protects protein-peptide drugs from hydrolysis in the acidic condition of the gastrointestinal tract [58,59,60,61], but binding of B12 to TC also facilitates B12–TC complex uptake via the TC receptor or CD320 [57]. As tissue B12 accumulation increased 350% upon overdosing of the vitamin [62], the use of B12 as a drug carrier could ensure a certain transport capacity.…”