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Examining the effects of vitamin B12 conjugation on the biological activity of insulin: a molecular dynamic and in vivo oral uptake investigation

Clardy-James, S., Allis, D.G., Fairchild, T.J. and Doyle, R.P. (2012) Examining the effects of vitamin B12 conjugation on the biological activity of insulin: a molecular dynamic and in vivo oral uptake investigation. MedChemComm, 3 (9). pp. 1054-1058.

Link to Published Version: http://dx.doi.org/10.1039/c2md20040f
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Abstract

The practical use of the vitamin B 12 uptake pathway to orally deliver peptides and proteins is much debated. To understand the full potential of the pathway however, a deeper understanding of the impact B 12 conjugation has on peptides and proteins is needed. We previously reported an orally active B 12 based insulin conjugate attached at LysB29 with hypoglycemic properties in STZ diabetic rats. We are exploring an alternative attachment for B 12 on insulin in an attempt to determine the effect B 12 has on the protein biological activity. We describe herein the synthesis, characterization, and purification of a new B 12-insulin conjugate, which is attached between the B 12 ribose hydroxyl group and insulin PheB1. The hypoglycemic properties resulting from oral administration (gavage) of such a conjugate in STZ diabetic rats was similar to that noted in a conjugate covalently linked at insulin LysB29, demonstrating the availability of both positions on insulin for B 12 attachment. A possible rationale for this result is put forward from MD simulations. We also conclude that there is a dose dependent response that can be observed for B 12-insulin conjugates, with doses of conjugate greater than 10 -9 M necessary to observe even low levels of glucose drop.

Publication Type: Journal Article
Murdoch Affiliation: School of Chiropractic and Sports Science
Publisher: Royal Society of Chemistry
Copyright: © 2012 The Royal Society of Chemistry
URI: http://researchrepository.murdoch.edu.au/id/eprint/10554
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